bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of HDAC6 protects against rhabdomyolysis-induced acute kidney injury
Authors: Shi Yingfeng , Xu Liuqing , Tang Jinhua , Fang Lu , Ma Shuchen , Ma Xiaoyan , Nie Jing , Pi Xiaoling , Qiu Andong , Zhuang Shougang , Liu Na
Published: January 2017

Histone deacetylase 6 (HDAC6) inhibition has been reported to protect against ischemic stroke and prolong survival after sepsis in animal models. However, it remains unknown whether HDAC6 inhibition offers a renoprotective effect after acute kidney injury (AKI). In this study, we examined the effect of tubastatin A (TA), a highly selective inhibitor of HDAC6, on AKI in a murine model of glycerol (GL) injection-induced rhabdomyolysis. Following GL injection, the mice developed severe acute tubular injury as indicated by renal dysfunction; expression of neutrophil gelatinase-associated lipocalin (NGAL), an injury marker of renal tubules; and an increase of TdT-mediated dUTP nick-end labeling (TUNEL)-positive tubular cells. These changes were companied by increased HDAC6 expression in the cytoplasm of renal tubular cells. Administration of TA significantly reduced serum creatinine and blood urea nitrogen levels as well as attenuated renal tubular damage in injured kidneys. HDAC6 inhibition also resulted in decreased expression of NGAL, reduced apoptotic cell, and inactivated caspase-3 in the kidney after acute injury. Moreover, injury to the kidney increased phosphorylation of nuclear factor (NF)-κB and expression of multiple cytokines/chemokines including tumor necrotic factor-α and interleukin-6 and monocyte chemoattractant protein-1, as well as macrophage infiltration. Treatment with TA attenuated all those responses. Finally, HDAC6 inhibition reduced the level of oxidative stress by suppressing malondialdehyde (MDA) and preserving expression of superoxide dismutase (SOD) in the injured kidney. Collectively, these data indicate that HDAC6 contributes to the pathogenesis of rhabdomyolysis-induced AKI and suggest that HDAC6 inhibitors have therapeutic potential for AKI treatment.
Polyneuropathy as Novel Initial Manifestation in a Case of “Nonsecretory” POEMS Syndrome with Sjögren’s Syndrome
Authors: Liang Minrui , Jiang Zhixing , Lin Zhiguang , Chen Bobin , Zou Hejian , Wan Weiguo , Liu Jun
Published: January 2017

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) is a paraneoplastic syndrome driven by plasma cell dyscrasias. We report a patient with novel initial manifestation of polyneuropathy, which was considered due to Sjögren’s syndrome but with poor response to methylprednisolone (120 mg/d) and intravenous immunoglobulin (IVIg). Further investigation by imaging tests and following biopsy eventually confirmed the diagnosis of POEMS syndrome secondary to solitary plasmocytoma. To our knowledge, this is the first reported case of POEMS syndrome with Sjögren’s syndrome occurring in the absence of a peripheral monoclonal gammopathy, highlighting the diagnostic challenges posed by this disease and reviewing the diagnostic role of (18) F-FDG PET/CT in POEMS syndrome.
Horner Syndrome Secondary to Thyroid Surgery
Authors: Demiral Meliha , Binay Ciğdem , Simsek Enver , Ilhan Hüseyin
Published: January 2017

Horner syndrome (HS), caused by an interruption in the oculosympathetic pathway, is characterised by myosis, ipsilateral blepharoptosis, enophthalmos, facial anhydrosis, and vascular dilation of the lateral part of the face. HS is a rare complication of thyroidectomy. A 15-year-old female patient presented with solitary solid and large nodule in the right thyroid lobe. Ultrasound-guided fine-needle aspiration was performed and the cytological examination results were undefined. The patient underwent a total thyroidectomy. On postoperative day 2, she developed right-sided myosis and upper eyelid ptosis. HS was diagnosed. Interestingly, the patient exhibited an incomplete clinical syndrome with the absence of vasomotor symptoms. We herein report a case of HS in a 15-year-old female patient after total thyroidectomy. The possible causes of HS were ischaemia-induced nerve damage and stretching of the cervical sympathetic chain by the retractor during thyroidectomy. Clinicians should be aware of the possibility of this rare but important surgical complication.
Assessment of Serum Vascular Endothelial Growth Factor Levels in Pregnancy-Induced Hypertension Patients
Authors: Tandon Vibha , Hiwale Swati , Amle Dnyanesh , Nagaria Tripti , Patra Pradeep Kumar
Published: January 2017

Objective. The objective of the study was to assess the serum vascular endothelial growth factor (VEGF) levels in peripheral blood of patients with pregnancy-induced hypertension (PIH) and find association between serum VEGF levels and PIH.Methods. Thirty-five PIH subjects, 35 normal pregnant females, and 20 normal healthy females were included in the study. Detailed history, clinical examination, and relevant biochemical parameters were assessed; serum VEGF levels were estimated using Double-antibody enzyme-linked immunosorbent assay.Results. The study groups were found to be age matched (p=0.38). VEGF level in the pregnancy-induced hypertensive group (median = 109.19 (3.38±619)) was significantly higher than the normal pregnant (median = 20.82 (1.7–619)) and control (median = 4.92 (1.13–13.07)) group and the difference between these three groups was significant (p<0.0001). The 3 groups are found to be significantly different in terms of RBS (p=0.01), urea (p<0.0001), creatinine (p=0.0005), AST (p=0.0032), ALT (p=0.0007), total protein (p=0.0004), albumin (p<0.0001), calcium (p=0.001), and sodium (p=0.02), while no statistically significant difference was found between total bilirubin (p=0.167), direct bilirubin (p=0.07), uric acid (p=0.16), and potassium (p=0.14).Conclusion. Significantly higher levels of serum VEGF were noted in PIH subjects compared to normal pregnant and control subjects.
High Levels of Hemoglobin Promote Carotid Adventitial Vasa Vasorum Neoangiogenesis in Chronic Kidney Disease
Authors: Arcidiacono Maria Vittoria , Martinez-Alonso Montserrat , Belart Montserrat , Vilar Ana , Martín Marisa , Craver Lourdes , Betriu Àngels , Mauricio Dídac , Valdivielso José Manuel , Fernández Elvira , Borràs Mercè
Published: January 2017

Chronic kidney disease (CKD) patients, characterized by traditional and nontraditional risk factors, are prone to develop atheromatosis and thus cardiovascular events and mortality. The angiogenesis of the adventitial vasa vasorum (aVV) surrounding the carotid has been described as the atheromatosis initiator. Therefore, the aim of the study was to (1) evaluate if the carotid aVV in CKD patients increases in comparison to its physiological value of healthy patients; (2) explore which traditional or nontraditional risk factor including inflammation, bone and mineral metabolism, and anemia could be related to the aVV angiogenesis. CKD patients without previous cardiovascular events (44, stages 3-4; 37, stage 5D) and 65 healthy subjects were compared. The carotid aVV and the intima-media thickness (cIMT) were evaluated by ultrasound. CKD patients at stages 3-4 showed higher aVV of the right carotid artery even after adjusting for age. Importantly, a multiple linear regression model showed hemoglobin levels > 12.5 g/dL as the factor for an estimated higher aVV of the right carotid artery. In conclusion, the association of hemoglobin with higher aVV could suggest the role of high hemoglobin in the higher incidence of adverse cardiovascular outcomes in CKD patients.
General and Specific Genetic Polymorphism of Cytokines-Related Gene in AITD
Authors: Xiaoheng Chen , Yizhou Mei , Bei He , Huilong Li , Xin Wang , Rui Hu , Lu Li , Zhiguo Ding
Published: January 2017

Autoimmune thyroid disease (AITD) shows the highest incidence among organ-specific autoimmune diseases and is the most common thyroid disease in humans, including Graves’ disease (GD) and Hashimoto’s thyroiditis (HT). The susceptibility to autoimmune diseases is affected by increased autoantibody levels, susceptibility gene polymorphisms, environmental factors, and psychological factors, but the pathogenesis remains unclear. Various cytokines and related genes encoding them play important roles in the development and progression of AITD. CD152, an expression product of the CTLA-4 gene, downregulates T cell activation. The A/A genotype polymorphism in the CT60 locus may reduce the production of thyroid autoantibodies. The C1858T polymorphism of the PTNP22 gene reduces the expression of its encoded LYP, which increases the risk of GD and HT. GD is an organ-specific autoimmune disease involving increased secretion of thyroid hormone, whereas HT may be associated with the destruction of thyroid gland tissue and hypothyroidism. These two diseases exhibit similar pathogenesis but opposite trends in the clinical manifestations. In this review, we focus on the structure and function of these cytokines and related genes in AITD, as well as the association of polymorphisms with susceptibility to GD and HT, and attempt to describe their differences in pathogenesis and clinical manifestations.
Activation of the Nrf2‐Keap 1 Pathway in Short‐Term Iodide Excess in Thyroid in Rats
Authors: Wang Tingting , Liang Xue , Abeysekera Iruni Roshanie , Iqbal Umar , Duan Qi , Naha Gargi , Lin Laixiang , Yao Xiaomei
Published: January 2017

Wistar rats were randomly divided into groups of varying iodide intake: normal iodide; 10 times high iodide; and 100 times high iodide on Days 7, 14, and 28. Insignificant changes were observed in thyroid hormone levels (p > 0.05). Urinary iodine concentration and iodine content in the thyroid glands increased after high consumption of iodide from NI to 100 HI (p < 0.05). The urinary iodine concentration of the 100 HI group on Days 7, 14, and 28 was 60–80 times that of the NI group. The mitochondrial superoxide production and expressions of Nrf2, Srx, and Prx 3 all significantly increased, while Keap 1 significantly decreased in the 100 HI group when compared to the NI or 10 HI group on Days 7, 14, and 28 (p < 0.05). Immunofluorescence staining results showed that Nrf2 was localized in the cytoplasm in NI group. Although Nrf2 was detected in both cytoplasm and nucleus in 10 HI and 100 HI groups, a stronger positive staining was found in the nucleus. We conclude that the activation of the Nrf2‐Keap 1 antioxidative defense mechanism may play a crucial role in protecting thyroid function from short‐term iodide excess in rats.
Dynamics of a Computer Virus Propagation Model with Delays and Graded Infection Rate
Authors: Zhang Zizhen , Song Limin
Published: January 2017

A four-compartment computer virus propagation model with two delays and graded infection rate is investigated in this paper. The critical values where a Hopf bifurcation occurs are obtained by analyzing the distribution of eigenvalues of the corresponding characteristic equation. In succession, direction and stability of the Hopf bifurcation when the two delays are not equal are determined by using normal form theory and center manifold theorem. Finally, some numerical simulations are also carried out to justify the obtained theoretical results.
The Double Layer Methodology and the Validation of Eigenbehavior Techniques Applied to Lifestyle Modeling
Authors: Schiavone Giuseppina , Lamichhane Bishal , Van Hoof Chris
Published: January 2017

A novel methodology, the double layer methodology (DLM), for modeling an individual’s lifestyle and its relationships with health indicators is presented. The DLM is applied to model behavioral routines emerging from self-reports of daily diet and activities, annotated by 21 healthy subjects over 2 weeks. Unsupervised clustering on the first layer of the DLM separated our population into two groups. Using eigendecomposition techniques on the second layer of the DLM, we could find activity and diet routines, predict behaviors in a portion of the day (with an accuracy of 88% for diet and 66% for activity), determine between day and between individual similarities, and detect individual’s belonging to a group based on behavior (with an accuracy up to 64%). We found that clustering based on health indicators was mapped back into activity behaviors, but not into diet behaviors. In addition, we showed the limitations of eigendecomposition for lifestyle applications, in particular when applied to noisy and sparse behavioral data such as dietary information. Finally, we proposed the use of the DLM for supporting adaptive and personalized recommender systems for stimulating behavior change.
A Case-Control Study of Risk Factors for Salivary Gland Cancer in Canada
Authors: Pan Sai Yi , de Groh Margaret , Morrison Howard
Published: January 2017

Aim. To assess the effect of various lifestyle risk factors on the risk of salivary gland cancer in Canada using data from a population-based case-control study.Methods. Data from a population-based case-control study of 132 incident cases of salivary gland cancer and 3076 population controls were collected through self-administered questionnaire and analysed using unconditional logistic regression.Results. Four or more servings/week of processed meat product was associated with an adjusted odds ratio (OR) and corresponding 95% confidence interval (CI) of 1.62 (1.02–2.58). Nonsignificantly increased ORs were also related to obesity, >7 drinks/week of alcohol consumption, and occupational exposure to radiation. Furthermore, nonsignificantly decreased ORs were found to be associated with high education level (>12 years) (OR=0.65), high consumption of spinach/squash (OR=0.62) and all vegetables/vegetable juices (OR=0.75), and >30 sessions/month of recreational physical activity (OR=0.78).Conclusions. This study suggests positive associations with consumption of processed meat, smoking, obesity, alcohol drinking, and occupational exposure to radiation as well as negative associations with higher education, consumption of spinach/squash, and physical activity, which suggest a role of lifestyle factors in the etiology of salivary gland cancer. However, these findings were based on small number of cases and were nonsignificant. Further larger studies are warranted to confirm our findings.
Nanostructured Semiconductor Materials for Dye-Sensitized Solar Cells
Authors: Cavallo Carmen , Di Pascasio Francesco , Latini Alessandro , Bonomo Matteo , Dini Danilo
Published: January 2017

Since O’Regan and Grätzel’s first report in 1991, dye-sensitized solar cells (DSSCs) appeared immediately as a promising low-cost photovoltaic technology. In fact, though being far less efficient than conventional silicon-based photovoltaics (being the maximum, lab scale prototype reported efficiency around 13%), the simple design of the device and the absence of the strict and expensive manufacturing processes needed for conventional photovoltaics make them attractive in small-power applications especially in low-light conditions, where they outperform their silicon counterparts. Nanomaterials are at the very heart of DSSC, as the success of its design is due to the use of nanostructures at both the anode and the cathode. In this review, we present the state of the art for bothn-type andp-type semiconductors used in the photoelectrodes of DSSCs, showing the evolution of the materials during the 25 years of history of this kind of devices. In the case ofp-type semiconductors, also some other energy conversion applications are touched upon.
Is Month of Birth a Risk Factor for Colorectal Cancer?
Authors: Francis N. K. , Curtis N. J. , Noble E. , Cortina-Borja M. , Salib E.
Published: January 2017

Introduction. The developmental origins of health and disease hypothesis and season of birth have been linked to a wide variety of later life conditions including cancer. Whether any relationship between month and season of birth and colorectal cancer exists is unknown. Methods. A case-control study was performed with month of birth extracted from a dedicated colorectal cancer database. Age and gender matched patients were used as a control group. Generalised linear models were fitted with Poisson and negative binomial responses and logarithmic links. A forward stepwise approach was followed adding seasonal components with 6- and 12-month periods. Results. 1019 colorectal cancer patients and 1277 randomly selected age and gender matched controls were included. For both men and women there is an excess of colorectal cancer in those born in autumn and a corresponding reduction of risk among those born in spring (p = 0.026). For the identified September peak, the excess risk for colorectal cancer was 14.8% (95% CI 5.6–32.3%) larger than the spring trough. Conclusion. There is a seasonal effect in the monthly birth rates of people who are operated for colorectal cancer with a disproportionate excess of cancer in those born in September. Further large studies are required to validate these findings.
The Effectiveness of Aromatherapy for Depressive Symptoms: A Systematic Review
Authors: Sánchez-Vidaña Dalinda Isabel , Ngai Shirley Pui-Ching , He Wanjia , Chow Jason Ka-Wing , Lau Benson Wui-Man , Tsang Hector Wing-Hong
Published: January 2017

Background. Depression is one of the greatest health concerns affecting 350 million people globally. Aromatherapy is a popular CAM intervention chosen by people with depression. Due to the growing popularity of aromatherapy for alleviating depressive symptoms, in‐depth evaluation of the evidence‐based clinical efficacy of aromatherapy is urgently needed. Purpose. This systematic review aims to provide an analysis of the clinical evidence on the efficacy of aromatherapy for depressive symptoms on any type of patients. Methods. A systematic database search was carried out using predefined search terms in 5 databases: AMED, CINHAL, CCRCT, MEDLINE, and PsycINFO. Outcome measures included scales measuring depressive symptoms levels. Results. Twelve randomized controlled trials were included and two administration methods for the aromatherapy intervention including inhaled aromatherapy (5 studies) and massage aromatherapy (7 studies) were identified. Seven studies showed improvement in depressive symptoms. Limitations. The quality of half of the studies included is low, and the administration protocols among the studies varied considerably. Different assessment tools were also employed among the studies. Conclusions. Aromatherapy showed potential to be used as an effective therapeutic option for the relief of depressive symptoms in a wide variety of subjects. Particularly, aromatherapy massage showed to have more beneficial effects than inhalation aromatherapy.
Endoscopic Resection of Skull Base Teratoma in Klippel-Feil Syndrome through Use of Combined Ultrasonic and Bipolar Diathermy Platforms
Authors: Edward Justin A. , Psaltis Alkis J. , Williams Ryan A. , Charville Gregory W. , Dodd Robert L. , Nayak Jayakar V.
Published: January 2017

Klippel-Feil syndrome (KFS) is associated with numerous craniofacial abnormalities but rarely with skull base tumor formation. We report an unusual and dramatic case of a symptomatic, mature skull base teratoma in an adult patient with KFS, with extension through the basisphenoid to obstruct the nasopharynx. This benign lesion was associated with midline palatal and cerebral defects, most notably pituitary and vertebrobasilar arteriolar duplications. A multidisciplinary workup and a complete endoscopic, transnasal surgical approach between otolaryngology and neurosurgery were undertaken. Out of concern for vascular control of the fibrofatty dense tumor stalk at the skull base and need for complete teratoma resection, we successfully employed a tissue resection tool with combined ultrasonic and bipolar diathermy to the tumor pedicle at the sphenoid/clivus junction. No CSF leak or major hemorrhage was noted using this endonasal approach, and no concerning postoperative sequelae were encountered. The patient continues to do well now 3 years after tumor extirpation, with resolution of all preoperative symptoms and absence of teratoma recurrence. KFS, teratoma biology, endocrine gland duplication, and the complex considerations required for successfully addressing this type of advanced skull base pathology are all reviewed herein.
Series-Based Solution for Analysis of Simply Supported Rectangular Thin Plate with Internal Rigid Supports
Authors: Musa Abubakr E. S. , Al-Gahtani Husain J.
Published: January 2017

In this study, Navier’s solution for the analysis of simply supported rectangular plates is extended to consider rigid internal supports. The proposed method offers a more accurate solution for the bending moment at the critical section and therefore serves as a better analytical solution for design purposes. To model the plate-support interaction, the patched areas representing the contact between the plate and supports are divided into groups of cells. The unknown internal reactions at the centers of the divided cells are obtained by satisfying the compatibility conditions at the centers of the cells. Three numerical examples are presented to demonstrate the accuracy of the proposed analytical solution. The given examples reveal good agreements with those obtained by the finite element analysis. In addition, they show the advantage of the new solution as compared to the existing analytical solution which inaccurately estimates the location and magnitude of the maximum bending moment.
An Assessment of Vitreous Degeneration in Eyes with Vitreomacular Traction and Macular Holes
Authors: Ghadiali Quraish , Zahid Sarwar , Dolz-Marco Rosa , Tan Anna , Engelbert Michael
Published: January 2017

Purpose. To compare the stages of vitreous degeneration in patients with vitreomacular traction (VMT) and macular holes (MH). Methods. A retrospective study was performed analyzing stages of vitreous degeneration of eyes with VMT or MH using swept-source optical coherence tomography (SS-OCT) and spectral-domain optical coherence tomography (SD-OCT). An analogous review was performed on a control group of eyes with contralateral posterior vitreous detachments. Thirty-four eyes with VMT/MH and 39 control eyes were reviewed. Results. Twenty-seven VMT/MH eyes and 31 control eyes were included. Eyes with VMT/MH demonstrated significantly earlier stages of vitreous degeneration when compared to the control group (p=0.048) despite significantly greater age (p=0.032). Conclusions. Vitreoretinal interface disease is more often associated with a formed vitreous and an intact premacular bursa. This is contrary to previous assumptions implicating degeneration of vitreous as a precipitating factor of interface disease when in conjunction with abnormal vitreomacular separation.
Water Soluble Fluorescent Carbon Nanodots from Biosource for Cells Imaging
Authors: Tripathi Kumud Malika , Tran Tuan Sang , Tung Tran Thanh , Losic Dusan , Kim TaeYoung
Published: January 2017

Carbon nanodots (CNDs) derived from a green precursor, kidney beans, was synthesized with high yield via a facile pyrolysis technique. The CND material was easily modified through simple oxidative treatment with nitric acid, leading to a high density “self-passivated” water soluble form (wsCNDs). The synthesized wsCNDs have been extensively characterized by using various microscopic and spectroscopic techniques and were crystalline in nature. The highly carboxylated wsCNDs possessed tunable-photoluminescence emission behavior throughout the visible region of the spectrum, demonstrating their application for multicolor cellular imaging of HeLa cells. The tunable-photoluminescence properties of “self-passivated” wsCNDs make them a promising candidate as a probe in biological cell-imaging applications.
Soft Tissue Schwannomas of the Hard Palate and the Mandibular Mentum
Authors: Eroglu Cennet Neslihan , Keskin Tunc Serap , Gunhan Omer
Published: January 2017

Schwannomas are benign, slow growing, encapsulated tumours that originate from the Schwann cells. Intraoral schwannomas are rare, and most of these tumours involve the tongue. They are rarely located in the hard palate or in the facial soft tissue. Herein, we present the clinical and histological features as well as the prognoses of two male patients with schwannoma, one of which was localized to the hard palate and the other to the facial soft tissue around the mandibular mentum and caused swelling.
Metformin and Diammonium Glycyrrhizinate Enteric-Coated Capsule versus Metformin Alone versus Diammonium Glycyrrhizinate Enteric-Coated Capsule Alone in Patients with Nonalcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus
Authors: Zhang Rong , Cheng Keran , Xu Shizan , Li Sainan , Zhou Yuqing , Zhou Shunfeng , Kong Rui , Li Linqiang , Li Jingjing , Feng Jiao , Wu Liwei , Liu Tong , Xia Yujing , Lu Jie , Guo Chuanyong , Zhou Yingqun
Published: January 2017

Objective. The present study was conducted to compare the efficacy of metformin combined with diammonium glycyrrhizinate enteric-coated capsule (DGEC) versus metformin alone versus DGEC alone for the treatment of nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). Subjects and Methods. 163 patients with NAFLD and T2DM were enrolled in this 24-week study and were randomized to one of three groups: group 1 was treated with metformin alone; group 2 was treated with DGEC alone; group 3 received metformin plus DGEC combination therapy. Anthropometric parameters, liver function, lipid profile, serum ferritin (SF), metabolic parameters, liver/spleen computed tomography (CT) ratio, and fibroscan value were evaluated at baseline and after 8, 16, and 24 weeks of treatment. Results. After 24 weeks, significant improvements in all measured parameters were observed in three groups (P<0.05) except for the improvements in low density lipoprotein cholesterol (LDL-C) and metabolic parameters in group 2 which did not reach statistical significance (P>0.05). Compared with group 1 and group 2, the patients in group 3 had greater reductions in observed parameters apart from CB and TB (P<0.05). Conclusions. This study showed that metformin plus DGEC was more effective than metformin alone or DGEC alone in reducing liver enzymes, lipid levels, and metabolic parameters and ameliorating the degree of hepatic fibrosis in patients with NAFLD and T2DM.
Idiosyncratic Drug-Induced Liver Injury (IDILI): Potential Mechanisms and Predictive Assays
Authors: Roth Alexander D. , Lee Moo-Yeal
Published: January 2017

Idiosyncratic drug-induced liver injury (IDILI) is a significant source of drug recall and acute liver failure (ALF) in the United States. While current drug development processes emphasize general toxicity and drug metabolizing enzyme- (DME-) mediated toxicity, it has been challenging to develop comprehensive models for assessing complete idiosyncratic potential. In this review, we describe the enzymes and proteins that contain polymorphisms believed to contribute to IDILI, including ones that affect phase I and phase II metabolism, antioxidant enzymes, drug transporters, inflammation, and human leukocyte antigen (HLA). We then describe the various assays that have been developed to detect individual reactions focusing on each of the mechanisms described in the background. Finally, we examine current trends in developing comprehensive models for examining these mechanisms. There is an urgent need to develop a panel of multiparametric assays for diagnosing individual toxicity potential.
Single-Session Combined Anterior-Posterior Approach for Treatment of Ankylosing Spondylitis with Obvious Displaced Lower Cervical Spine Fractures and Dislocations
Authors: Yang Baohui , Lu Teng , Li Haopeng
Published: January 2017

For patients with AS and lower cervical spine fractures, surgical methods have mainly included the single anterior approach, single posterior approach, and combined anterior-posterior approach. However, various surgical procedures were utilized because the fractures have not been clearly classified according to presence of displacement in these previous studies. Consequently, controversies have been raised regarding the selection of the surgical procedure. This study retrospective analysis was conducted in 12 patients with AS and lower cervical spine fractures and dislocations and explored single-session combined anterior-posterior approach for the treatment of AS with obvious displaced lower cervical spine fractures and dislocations which has demonstrated advantages such as good stabilization, satisfied fracture healing, and easy postoperative cares. However, to some extent, the difficulty and risk of this approach should be considered. Attention should be paid to the prevention of perioperative complications.
A Simple and Improved HPLC-PDA Method for Simultaneous Estimation of Fexofenadine and Pseudoephedrine in Extended Release Tablets by Response Surface Methodology
Authors: Kayesh Ruhul , Sarker A. S. M. Moniruzzaman , Sultan Md. Zakir , Jahan Md. Sarowar
Published: January 2017

A simple RP-HPLC method has been developed for simultaneous estimation of fexofenadine and pseudoephedrine in their extended release tablet. The method was developed based on statistical design of experiments (DoE) and Response Surface Methodology. Separation was achieved on double end-capped C18 column (250 mm × 4 mm, 5 μm). In this experiment, two components of mobile phase, namely, acetonitrile (% v/v) and methanol (% v/v), were the factors whereas retention and resolution of the chromatographic peaks were the responses. The effects of different composition of factors on the corresponding responses were investigated. The optimum chromatographic condition for the current case was found as an isocratic mobile phase consisting of 20 mM phosphate buffer (pH 6.8) and acetonitrile and methanol in a ratio of 50 : 36 : 14 (% v/v) at a flow rate of 1 mL/min for 7 minutes. The retention of pseudoephedrine and fexofenadine was found to be 2.6 min and 4.7 min, respectively. The method was validated according to the ICH and FDA guidelines and various validation parameters were determined. Also, forced degradation studies in acid, base, oxidation, and reduction media and in thermal condition were performed to establish specificity and stability-indicating property of this method. Practical applicability of this method was checked in extended release tablets available in Bangladeshi market.
Abstract A11: Therapeutic targeting of GCB- and ABC-DLBCLS by rationally designed BCL6 inhibitors
Authors: Cardenas Mariano Gonzalo , Yu Wenbo , Beguelin Wendy , Matthew Teater R. , Geng Huimin , Goldstein Rebecca , Oswald Erin , Hatzi Katerina , Yang Shao-Ning , Cohen Joanna , Shaknovich Rita , Vanommeslaeghe Kenno , Cheng Huimin , Liang Dongdong , Cho Hyoje , Abbott Joshua , Tam Wayne , Leonard John P. , Cerchietti Leandro , Cierpicki Tomasz , Xue Fengtian , MacKerell Alexander D. , Melnick Ari
Published: January 2017

Rationale: The BCL6 oncogene is constitutively activated by chromosomal translocations and amplification in ABC-DLBCLs, a class of DLBCLs that respond poorly to current therapies. Yet the role of BCL6 in maintaining these lymphomas has not been investigated. BCL6 mediates its effects by recruiting corepressors to an extended groove motif. Development of effective BCL6 inhibitors requires compounds exceeding the binding affinity of these corepressors.

Objectives: To design small molecule inhibitors with superior potency vs. endogenous BCL6 ligands for unmet putative therapeutic needs such as targeting ABC-DLBCL.

Findings: We used an in silico drug design functional-group mapping approach called SILCS to create a specific BCL6 inhibitor with 10-fold greater potency than endogenous corepressors. The compound, called FX1, binds in such a way as to occupy an essential region of the BCL6 lateral groove. FX1 disrupts BCL6 repression complex formation, reactivates BCL6 target genes, and mimics the phenotype of mice engineered to express BCL6 with lateral groove mutations. This compound eradicated established DLBCLs xenografts at low doses. Most strikingly, FX1 suppressed ABC-DLBCL cells as well as primary human ABC-DLBCL specimens ex vivo.

Conclusions: ABC-DLBCL is a BCL6 dependent disease that can be targeted by novel inhibitors able to exceed the binding affinity of natural BCL6 ligands.

Citation Format: Mariano Gonzalo Cardenas, Wenbo Yu, Wendy Beguelin, Teater R. Matthew, Huimin Geng, Rebecca Goldstein, Erin Oswald, Katerina Hatzi, Shao-Ning Yang, Joanna Cohen, Rita Shaknovich, Kenno Vanommeslaeghe, Huimin Cheng, Dongdong Liang, Hyoje Cho, Joshua Abbott, Wayne Tam, John P. Leonard, Leandro Cerchietti, Tomasz Cierpicki, Fengtian Xue, Alexander D. MacKerell, Jr., Ari Melnick. Therapeutic targeting of GCB- and ABC-DLBCLS by rationally designed BCL6 inhibitors. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A11.
Abstract A30: Kinome dynamics in triple negative breast cancer in response to chemotherapy
Authors: Velarde Sara H. , Usary Jerry , Perou Chuck , Johnson Gary L.
Published: January 2017

Triple negative breast cancers (TNBC) have lower expression levels of the receptors (estrogen, progesterone, Her2) used in targeted therapy than other breast cancer subtypes. This makes chemotherapy the main option for treatment for TNBC patients. Only about 22% of TNBC patients respond to chemotherapy, so it is important to understand the tumor cell response involved in TNBC chemo-resistance in order to develop more effective therapies. We have studied the kinome response to paclitaxel and carboplatin in tumor samples derived from TNBC patients in both HIM PDXs (Human-In-Mouse Patient Derived Xenografts) and cell lines derived from HIM PDX lines. Integration of RNAseq and Multiplexed Inhibitor Bead/Mass Spectrometry (MIB/MS) analysis of kinome dynamics in HIM PDXs in response to carboplatin and paclitaxel treatment identified multiple pathways whose expression and/or MIB binding dynamics were changed or altered after chemotherapy. Multiple survival and apoptotic regulators, including NFkB, JNK, ErbB, Sonic Hedgehog and Hippo pathways, were altered over the course of chemotherapy treatment. We are interrogating these pathways in both the HIM PDXs and HIM cell lines to determine each pathway's role in chemosensitivity with the goal of developing pharmacological strategies to increase the efficacy of chemotherapy, as well as kinase inhibitors, in the clinic.

Citation Format: Sara H. Velarde, Jerry Usary, Chuck Perou, Gary L. Johnson. Kinome dynamics in triple negative breast cancer in response to chemotherapy. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A30.
Abstract B01: Integrated genomic analysis identifies two subsets of cervical cancer with potentially distinct therapeutic profiles
Authors: Banister Carolyn E. , Pirisi Lucia , Creek Kim E. , Buckhaults Phillip J.
Published: January 2017

Background and Significance: The continuous expression of HPV oncogenes is responsible for initiating and driving cervical cancer. Current treatments include radiation and Cisplatin-based chemotherapy. Targeted therapies can be directed to specific subset of tumors if they are known.

Methods: Molecular genetic data generated by The Cancer Genome Atlas (TCGA) were analyzed.

Results: We discovered and characterized a subset of HPV positive cervical cancers that do not express HPV transcripts, including the E6 and E7 oncogenes. These tumors more commonly appear in women with a median age of diagnosis 9 years later (54 vs. 45 years) (p-value = 0.023) and reveal worse survival (p-value 0.06). Gene expression profiles of HPV expressing tumors (HPV-active) are distinct from those tumors that do not express HPV (HPV-inactive). Gene Set Enrichment Analysis of the HPV-active tumors show enrichment for E2F target genes, as expected based on the activity of HPV E7. HPV-inactive tumors show enrichment for WNT/beta-catenin target genes. Additionally, this analysis reveals that the HPV-active tumors have increased AKT/MTOR signaling and HPV-inactive tumors have increased sonic hedgehog signaling indicating different potential therapeutic targets for these two classes of tumors. The majority of differentially expressed genes can be explained by DNA hyper methylation and silencing of expression. Somatic mutation landscapes are significantly different. HPV-inactive tumors are significantly enriched for non-synonymous somatic mutations (p-value <0.0000001) compared to HPV-active tumors.

Conclusions: Many of the somatic mutations found in non-expressing tumors mimic the functions of the E6 and E7 viral oncoproteins, such as TP53, CTNNB1, EGFR and KRAS somatic mutations. Unexpectedly, BRCA1 and BRCA2 somatic mutations are more frequent in the HPV-inactive tumors. Therapeutic strategies based on PARP inhibition may be effective against this category of cervical cancers. Application of therapeutics routinely used in other cancer types could be used to exploit the weaknesses we discovered in the HPV-inactive tumors and may improve survival for these cervical cancer patients.

Citation Format: Carolyn E. Banister, Lucia Pirisi, Kim E. Creek, Phillip J. Buckhaults. Integrated genomic analysis identifies two subsets of cervical cancer with potentially distinct therapeutic profiles. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B01.
Abstract B07: Differential roles for AKT isoforms in BRAF mutant melanoma
Authors: McRee Siobhan K. , Pietruska Jodie R. , Dignan Elisabeth , Hinds Philip W.
Published: January 2017

Despite recent advances, melanoma remains the deadliest form of skin cancer, and new therapeutic strategies are urgently needed. The MAP kinase (MAPK) and PI3K/AKT pathways are central to both disease progression and chemoresistance in melanoma, with dual targeting approaches yielding promising results that would benefit from increased target specificity and selectivity. The AKT family of serine/threonine kinases comprises three highly homologous and functionally distinct isoforms (AKT1, AKT2, and AKT3) that play unique roles in melanoma but have not yet been leveraged for isoform-specific targeting.

Our lab has engineered a unique mouse model of melanoma, in which mutant BRAFV600E is constitutively targeted to mouse melanocytes, resulting in spontaneous malignant disease upon additional loss of tumor suppressor genes, and faithfully recapitulates the human disease. We have identified differential and dynamic activation of AKT isoforms in our mouse melanoma model, which supports the hypothesis that AKT isoforms may play both non-redundant and compensatory roles in melanoma progression. To systematically address this question, we have genetically ablated each AKT isoform individually in melanoma-prone mice in order to elucidate the individual and unique contribution of each isoform to melanoma progression.

In parallel, we performed in vitro studies using shRNA mediated conditional knockdown of AKTs in a wide variety of human melanoma cell lines. Our results support an isoform-specific role for AKT1 in promoting melanoma cell proliferation, while AKT2 stimulates cell migration. Further studies utilizing the precision genome editing technology CRISPR/Cas9 allows us to interrogate the effects of AKT isoform specific knockout (KO) on in vivo tumor formation. This work moves toward establishing the contribution of AKT isoforms to tumor progression in melanoma, using both human melanoma cell lines and mouse models, to advance our understanding of the role of AKT in melanomagenesis. With AKT inhibitors in clinical trials for melanoma, our findings could yield novel therapeutic strategies and increase the efficiency of existing therapies to improve treatment options and outcome for this devastating disease.

Citation Format: Siobhan K. McRee, Jodie R. Pietruska, Elisabeth Dignan, Philip W. Hinds. Differential roles for AKT isoforms in BRAF mutant melanoma. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B07.
Abstract B10: Synthetic lethal screen to identify novel therapies targeting TP53-mutant colon cancer cells
Authors: Weige Charles C. , Anderson Erin L. , Richardson Joseph , Contreras Carlo , Buckhaults Phillip J.
Published: January 2017

We have performed a genome-wide synthetic lethal screen for pathways that are essential for the survival of colon cancer cells with TP53 mutations. RKO colon cancer cells are wild-type for TP53, and display robust p53-dependent growth arrest and apoptosis. We have utilized an isogenic pair of RKO cells differing only in TP53 gene status (Wild Type vs homozygous null derivative) to screen a genome-wide GeCKO CRISPR library and identified pathways that are novel therapeutic targets for TP53-mutant colon cancers. After infection of these cells with the GeCKO CRISPR library and one week of culturing in vitro, we performed deep GeCKO CRIPSR amplicon sequencing to enumerate and identify all CRISPRs that were underrepresented in TP53 mutant compared to wild type cells. We identified multiple CRISPRs targeting the CHEK1 and the SHH genes which were underrepresented in TP53 knockout cells. We then tested small molecule inhibitors of CHEK1 (UCN01) and the SHH receptor SMO (Cyclopamine) against isogenic pairs of RKO, HCT116, and DLD1 cells and confirmed that each molecule is significantly more toxic to cells with mutant TP53 than to those with wild-type TP53. Future studies will focus on testing these and additional targets alone and in combination against primary colon tumor and normal avatars, and preclinical models of TP53-mutant colon cancer.

Citation Format: Charles C. Weige, Erin L. Anderson, Joseph Richardson, Carlo Contreras, Phillip J. Buckhaults. Synthetic lethal screen to identify novel therapies targeting TP53-mutant colon cancer cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B10.
Abstract B13: Reprogramming glioblastoma multiforme cells to neurons by protein kinase inhibitors
Authors: Yuan Jie , Zhang Fan , You Meng , Yang Qin
Published: January 2017

Reprogramming healthy somatic cells into pluripotent stem (iPS) cells with defined factors has been intensively investigated. However, reprogramming cancer cells has fallen much behind. Direct reversion of cancers into normal tissues is an ideal strategy for cancer treatment. Recent reports have showed that defined factors can induce reprogramming of cancer cells into iPS cells, supporting this notion. Glioblastoma multiforme (GBM) is the most common and most aggressive malignant primary brain tumor in humans. Despite multimodal therapy, the outcome for patients with GBM is still poor, with a median survival of just 14.2 months. Therefore, developing novel therapeutic strategy is an emergent task. The tumor suppressor p53 is considered today the most important tumor suppressor protein in humans and it suppresses both reprogramming and oncogenic transformation. p53 inactivation or mutations are the most common in GBM, and this p53 deficient GBM subgroup is currently the most difficult to treat, typically associated with rapid local recurrence after treatment. p53 mutations result in loss-of-function, gain-of-function, and dominant-negative mutational effects for p53. Thus, different p53 mutants may have various effects on reprogramming, promoting or inhibiting GBM reprogramming. Furthermore, p53 activity is often inactivated in GBM with wild-type p53 that may also affect reprogramming.

We have demonstrated that the depletion of p53 reprograms human somatic cells into neurons by regulation of a set of transcription factors (Nature Communications, 2014; Cell Reports, 2014, International Journal of Stem Cell Research & Therapy, 2016). Integration-free reprogramming cancer cells would be safer and preferable for clinical use. Along those lines, we screened a protein kinase inhibitor library and found that the kinase inhibitors can substitute for all transcription factors and convert human p53-deficient GBM cells into “normal” neurons (functional neurons). In vitro and in vivo tumorigenesis assays showed that induced neurons lose tumorigenicity. Moreover, the inhibitor reprogramming prevents GBM local recurrence in mice. Currently these inhibitors are used as anti-tumor drugs in patients, so this reprogramming strategy has significant potential to move rapidly toward clinical trials.

Note: This abstract was not presented at the conference.

Citation Format: Jie Yuan, Fan Zhang, Meng You, Qin Yang. Reprogramming glioblastoma multiforme cells to neurons by protein kinase inhibitors. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B13.
Abstract B22: Novel dual regulation of epithelial-mesenchymal transition and anoikis resistance prevents metastases of triple negative breast cancer
Authors: Ito Koichi , Park Sun Hee , Nayak Anupma , Irie Hanna Y.
Published: January 2017

Triple negative breast cancers (TNBC) are associated with a higher rate of metastatic recurrence and poorer prognosis due to intrinsic biological aggressiveness and lack of targeted therapies. Novel strategies to prevent metastasis are needed to improve outcomes for patients diagnosed with TNBC. Epithelial-mesenchymal transition (EMT) and anoikis resistance are processes recognized as contributing to treatment resistance and enhanced metastatic potential. In a functional genomic screen, we identified several candidates as novel dual regulators of EMT and anoikis sensitivity of triple negative breast cancer cells, that can be pharmacologically targeted to prevent metastases. One highly validated candidate, PTK6/Brk, specifically enhances anoikis resistance and metastatic potential of triple negative breast cancer cells via E-cadherin regulation. Overexpression of PTK6 in non-transformed immortalized breast epithelial cells is sufficient to promote an EMT, whereas PTK6 inhibition (either PTK6 shRNA or kinase inhibitor treatment) enhances E-cadherin expression and suppresses migration and lung colonization of TNBC cells. PTK6-dependent E-cadherin regulation and anoikis resistance is specifically dependent on levels of SNAIL, a transcriptional repressor. SNAIL down-regulation by PTK6 inhibition is directly responsible for modulation of anoikis sensitivity, which is in turn causally linked to lung colonization potential. PTK6 inhibition promotes the degradation of SNAIL via a novel mechanism independent of GSK3β and Fbox proteins known to regulate Snail ubiquitination. Using an siRNA screening approach, we identified novel E3 ligase candidates responsible for SNAIL ubiquitination and degradation downstream of PTK6 inhibition. PTK6 is a representative novel regulator of EMT and anoikis resistance that can be targeted to prevent metastases of patient triple negative tumors.

Citation Format: Koichi Ito, Sun Hee Park, Anupma Nayak, Hanna Y. Irie. Novel dual regulation of epithelial-mesenchymal transition and anoikis resistance prevents metastases of triple negative breast cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B22.