bluuebunny/crossref_metadata_2025_split huggingface dataset:
Radiation-Induced Malignant Transformation of Preneoplastic and Normal Breast Primary Epithelial Cells
Authors: Repullés Joan , Anglada Teresa , Soler David , Ramírez Juan Carlos , Genescà Anna , Terradas Mariona 
Published: January 2019

Abstract

Radiation is used in multiple procedures as a therapeutic and diagnostic tool. However, ionizing radiation can induce mutations in the DNA of irradiated cells, which can promote tumorigenesis. As malignant transformation is a process that takes many years, there are intermediate stages of cells that have initiated the process but have not yet evolved into cancer. The study here aimed to investigate the effect of ionizing radiation on normal and partially transformed human mammary epithelial cells. Breast primary epithelial cells were derived from normal breast tissue from two different donors and modified by transduction with the SV40 small and large T antigen and hTERT genes to obtain partially transformed cells and also with HRAS to completely and experimentally transform them. After exposure to different doses of ionizing radiation, oncogenic features were analyzed by means of an anchorage-independent growth assay and 3D cell culture. The addition of radiation exposure resulted in an increase in the number and size of colonies formed in each of the conditions analyzed and in the reduction of the capacity of partially transformed cells to form properly polarized 3D structures. Moreover, partially transformed cells require lower doses of radiation than healthy cells to enhance anchorage-independent growth capacity. Although cells from different donors have a different degree of sensitivity in the response to radiation, a higher sensitivity to the radiation-induced cell transformation process was observed in those cells that had already initiated the oncogenic process, which require higher doses of radiation to complete the transformation process.

Implications:
Individuals carrying accumulation of genetic alterations may have an increased susceptibility to radiation-induced neoplastic transformation.
The Germline Variants rs61757955 and rs34988193 Are Predictive of Survival in Lower Grade Glioma Patients
Authors: Chatrath Ajay , Kiran Manjari , Kumar Pankaj , Ratan Aakrosh , Dutta Anindya 
Published: January 2019

Abstract

Lower grade gliomas are invasive brain tumors that are difficult to completely resect neurosurgically. They often recur following resection and progress, resulting in death. Although previous studies have shown that specific germline variants increase the risk of tumor formation, no previous study has screened many germline variants to identify variants predictive of survival in patients with glioma. In this study, we present an approach to identify the small fraction of prognostic germline variants from the pool of over four million variants that we variant called in The Cancer Genome Atlas whole-exome sequencing and RNA sequencing datasets. We identified two germline variants that are predictive of poor patient outcomes by Cox regression, controlling for eleven covariates. rs61757955 is a germline variant found in the 3′ UTR of GRB2 associated with increased KRAS signaling, CIC mutations, and 1p/19q codeletion. rs34988193 is a germline variant found in the tumor suppressor gene ANKDD1a that causes an amino acid change from lysine to glutamate. This variant was found to be predictive of poor prognosis in two independent lower grade glioma datasets and is predicted to be within the top 0.06% of deleterious mutations across the human genome. The wild-type residue is conserved in all 22 other species with a homologous protein.

Implications:
This is the first study presenting an approach to screening many germline variants to identify variants predictive of survival and our application of this methodology revealed the germline variants rs61757955 and rs34988193 as being predictive of survival in patients with lower grade glioma.
LIN28/let-7/PD-L1 Pathway as a Target for Cancer Immunotherapy
Authors: Chen Yanlian , Xie Chen , Zheng Xiaohui , Nie Xin , Wang Zining , Liu Haiying , Zhao Yong 
Published: January 2019

Abstract
The immunocheckpoint protein PD-1/PD-L1 is considered a promising target for cancer immunotherapeutics. However, the objective response rate using antibodies that block the interaction between PD-1 and PD-L1 was less than 40%, and the mechanism underlying regulation of PD-1/PD-L1 expression is poorly understood. In this study, we identified the miRNA let-7 that posttranscriptionally suppresses PD-L1 expression. LIN28, an RNA binding protein upregulated in most cancer cells, inhibits the biogenesis of let-7, thus promoting PD-L1 expression. Therefore, inhibition of LIN28 may be a strategy to prevent immune evasion of cancer cells. We found that treatment with a LIN28 inhibitor, the small compound C1632, increases let-7 and suppresses PD-L1 expression, leading to reactivation of antitumor immunity in vitro and in vivo. In addition, C1632 also displayed the capacity to inhibit cancer cell proliferation and tumor growth in mice. Altogether, these findings identified LIN28/let-7 as a target for PD-L1–mediated immunotherapeutics and reveal the potential of C1632 and its derivatives as promising oncotherapeutic agents.
Antagonism of IAPs Enhances CAR T-cell Efficacy
Authors: Michie Jessica , Beavis Paul A. , Freeman Andrew J. , Vervoort Stephin J. , Ramsbottom Kelly M. , Narasimhan Vignesh , Lelliott Emily J. , Lalaoui Najoua , Ramsay Robert G. , Johnstone Ricky W. , Silke John , Darcy Phillip K. , Voskoboinik Ilia , Kearney Conor J. , Oliaro Jane 
Published: January 2019

Abstract
Chimeric antigen receptor (CAR) T-cell therapy has proven successful in the treatment of hematological malignancies, notably acute lymphoblastic leukemia and B-cell lymphoma. However, the efficacy of CAR T cells against solid tumors is poor, likely due to tumor-associated immunosuppression. Here, we demonstrated that antagonizing the “inhibitor of apoptosis proteins” with the clinical smac-mimetic, birinapant, significantly enhanced the antitumor activity of CAR T cells in a tumor necrosis factor (TNF)-dependent manner. Enhanced tumor cell death occurred independently of the perforin-mediated granule exocytosis pathway, underscoring the cytotoxic potential of CAR T-cell–derived TNF. Combining CAR T-cell therapy with birinapant significantly reduced established tumor growth in vivo, where either therapy alone was relatively ineffective. Using patient biopsy-derived tumoroids, we demonstrated the synergistic potential of combining CAR T-cell therapy with smac-mimetics. Taken together, we identified CAR T-cell–derived TNF as a potent antitumor effector, which can be further harnessed by smac-mimetics.
Growing teratoma syndrome in primary mediastinal germ cell tumor: our experience
Authors: Sachdeva Ashwani Kumar , Penumadu Prasanth , Kohli Pavneet , Dubashi Biswajit , Munuswamy Hemachandren 
Published: January 2019

Background Growing teratoma syndrome is a rare phenomenon seen in nonseminomatous germ cell tumors after chemotherapy, where the tumor grows paradoxically despite normalization of tumor markers. It has been found in various locations, most commonly, the retroperitoneum in association with metastatic disease. The occurrence of growing teratoma syndrome in a mediastinal primary is very rare and there are only a few reports in the literature. Methods In a retrospective review, out of 12 patients with mediastinal involvement by a germ cell tumor, 5 had a primary from the mediastinum. We present a series of 3 cases of primary germ cell tumor of the mediastinum, which after chemotherapy, fulfilled the criteria for growing teratoma syndrome and were managed with surgical excision. Conclusion Development of growing teratoma syndrome in a primary mediastinal germ cell tumor is extremely rare. Its awareness and early detection can lead to successful surgical excision and long-term cure.
Outcome measures in post-stroke arm rehabilitation trials: do existing measures capture outcomes that are important to stroke survivors, carers, and clinicians?
Authors: Duncan Millar Julie , van Wijck Frederike , Pollock Alex , Ali Myzoon 
Published: January 2019

Objective: We sought to (1) identify the outcome measures currently used across stroke arm rehabilitation randomized trials, (2) identify and compare outcomes important to stroke survivors, carers and clinicians and (3) describe where existing research outcome measures capture outcomes that matter the most to stroke survivors, carers and clinicians and where there may be discrepancies. Methods: First, we systematically identified and extracted data on outcome measures used in trials within a Cochrane overview of arm rehabilitation interventions. Second, we conducted 16 focus groups with stroke survivors, carers and clinicians using nominal group technique, supplemented with eight semi-structured interviews, to identify these stakeholders’ most important outcomes following post-stroke arm impairment. Finally, we described the constructs of each outcome measure and indicated where stakeholders’ important outcomes were captured by each measure. Results: We extracted 144 outcome measures from 243 post-stroke arm rehabilitation trials. The Fugl-Meyer Assessment Upper Extremity section (used in 79/243 trials; 33%), Action Research Arm Test (56/243; 23%), and modified Ashworth Scale (53/243; 22%) were most frequently used. Stroke survivors ( n = 43), carers ( n = 10) and clinicians ( n = 58) identified 66 unique, important outcomes related to arm impairment following stroke. Between one and three outcomes considered important by the stakeholders were captured by the three most commonly used assessments in research. Conclusion: Post-stroke arm rehabilitation research would benefit from a reduction in the number of outcome measures currently used, and better alignment between what is measured and what is important to stroke survivors, carers and clinicians.
The Effect of Previous Administration of Nizatidine on the Neuromuscular Effects of Vecuronium and the Effect of Nizatidine on Gastric Secretion
Authors: Wajima Z. , Shitara T. , Inoue T. , Yoshikawa T. , Ogawa R. 
Published: January 2019

Nizatidine, a new H2-receptor antagonist, has been reported to inhibit acetylcholinesterase activity. This could lead to an interaction with neuromuscular blocking drugs. This study examined the effects of nizatidine on the actions of vecuronium. Oral nizatidine has been reported to be an effective protective agent against acid aspiration syndrome, and we reevaluated this effect. The control group (n=10) received a placebo with water 50 ml and the nizatidine group (n=10) received nizatidine 300 mg with water 50 ml two hours before arrival in the operating room. Gastric contents were aspirated and the volume and pH measured before induction of anaesthesia. Anaesthesia was induced in all patients with thiopentone 5 mg/kg and 1.5% isoflurane in 98.5% oxygen followed by vecuronium 0.1 mg/kg. Vecuronium onset time and duration time 25 (time from injection until recovery of 25% of vaseline twitch amplitude) were obtained using electromyography. There were no significant differences between the two groups in vecuronium onset time or duration time 25. Gastric fluid volume was greater and gastric pH was lower in the control group than in the nizatidine group. 70% of the control group and none of the nizatidine group (P<0.005) had a gastric content pH <2.5 or volume >25 ml.
Tramadol for Postoperative Shivering: A Double-Blind Comparison with Pethidine
Authors: Bhatnagar S. , Saxena A. , Kannan T. R. , Punj J. , Panigrahi M. , Mishra S. 
Published: January 2019

In most operating and recovery rooms, shivering is controlled by the use of humidifiers, warming blankets, and inhalation of humidified heated oxygen. However, pharmacological control is an effective alternate treatment modality. This randomized, double-blind trial, conducted in 30 ASA Grade I or 2 patients, was designed to explore the efficacy of tramadol and pethidine in the treatment of post-anaesthetic shivering. Tramadol is an inhibitor of the re-uptake of serotonin (5-hydroxytryptamine) and norepinephrine in the spinal cord. This facilitates 5-hydroxytryptamine release, which influences thermoregulatory control. We compared the efficacy of tramadol with that of pethidine, presently a widely used drug for the control of shivering. Patients received either tramadol 1mg/kg or pethidine 0.5 mg/kg intravenously and the grade of shivering, pulse rate, blood pressure and respiratory rate were observed every 10 minutes after injection for one hour. Shivering was significantly more likely to have ceased in the tramadol group (12 of 15 versus 4 of 15 cases, P<0.05) at 10 minutes after drug administration and this control was better sustained. No patients receiving tramadol had a recurrence of shivering. It is concluded that intravenous tramadol 1 mg/kg is more effective for the treatment of postoperative shivering than pethidine 0.5 mg/kg.
Adrenocortical Response and Cortisone Replacement in Systemic Inflammatory Response Syndrome
Authors: Ihle B. U. 
Published: January 2019

The use of steroids as an adjunct to antimicrobial therapy has been controversial for many decades. Recent reports of the use of steroids in supraphysiological rather than in “industrial” doses in patients with sustained circulatory instability has re-ignited the debate. Anecdotal reports of adrenal insufficiency in septic patients have suggested a relative cortisol deficiency in these patients with poor survival if not given supplementary steroids. The possibility that the hypothalamic pituitary adrenal axis is intimately involved in the pathogenesis of this entity has not previously been highlighted. This review looks at the relationship of sustained cytokine release and the possibility of altering the stress response with progressive loss of adrenocorticotrophic hormone release and subsequent diminution in adequate cortisol levels. The reliance on, and misinterpretation of, the short synacthen test in diagnosing the possibility of this condition is emphasized.
Long-term Outcomes following Percutaneous Tracheostomy Using the Griggs Technique
Authors: Sviri S. , Samie R. , Roberts B. L. , Van Heerden P. V. 
Published: January 2019

Percutaneous tracheostomy is commonly performed in the intensive care unit. This study assesses the long-term outcomes following percutaneous tracheostomy using the Griggs technique. We carried out a prospective observational cohort study. Two hundred and eight patients who had undergone percutaneous tracheostomy between 1 September 1996 and 31 July 2000 and who were alive at least six months following the procedure, were included in the study. Median follow-up was at 30 months. All patients were sent questionnaires regarding relevant symptoms. One hundred and six (51%) responded and were invited for further follow-up. Forty-three (20.6%) patients underwent scar evaluation by the investigators and 41/208 (19.7%) underwent spirometry. Of the responders, 38% complained of some degree of voice change and 12% complained of ongoing severe cough. Thirty-one per cent complained of shortness of breath, with more than half of these having concomitant heart or lung disease, which may explain this. Eighty-one per cent of patients had minimally visible or a visible but neat scar. Eight patients (8/41 (19.5%)) had some evidence of upper airway obstruction on spirometry, but only 2/41 (5% of patients) were symptomatic (stridor or shortness of breath). We conclude that percutaneous tracheostomy using the Griggs technique has an acceptable long-term complication rate.
Clinical Evaluation of the HemoSonic Monitor in Cardiac Surgical Patients in the ICU
Authors: Moxon D. , Pinder M. , Van Heerden P. V. , Parsons R. W. 
Published: January 2019

The HemoSonic monitor (HemoSonic 100™, Arrow International, Reading, PA, U.S.A.) is a minimally invasive device to determine cardiac output by means of M-mode and pulsed Doppler ultrasound. We evaluated the HemoSonic monitor by comparing its output to paired measurements obtained by the standard thermodilution technique in patients who had recently undergone cardiac surgery. Forty-seven paired measurements were carried out in 13 patients. The correlation between the two methods was very good with a correlation coefficient of 0.81. Comparison of the two techniques using the method described by Bland and Altman showed a mean of the differences of –0.23. The limits of agreement were –2.35 to 1.89. There was a reduced correlation between techniques at higher values of cardiac output. We concluded that the HemoSonic monitor has a place in intensive care monitoring, with good correlation with cardiac output measured by the thermodilution technique. It appears to be less suitable for use in patients with a high cardiac output state. The oesophageal probe is moderately difficult for patients to tolerate and is only appropriate for use in sedated patients. The accuracy of the device is somewhat operator-dependent.
Comparison of Propofol Consumption and Recovery Time in Caucasians from Italy, with Chinese, Malays and Indians from Malaysia
Authors: Ortolani O. , Conti A. , Chan Y. K. , Sie M. Y. , Ong G. S. Y. 
Published: January 2019

Differences in sensitivity to anaesthetic drugs may exist among different ethnic groups. Allelic variants for drug metabolizing isoenzymes and pharmacokinetic differences may account for a variable response to some anaesthetic drugs. This study was designed to compare propofol consumption and recovery characteristics in four ethnic groups: Chinese, Malays, and Indians in Malaysia and Caucasians in Italy. Patients undergoing total intravenous anaesthesia with propofol and fentanyl were evaluated for propofol consumption and recovery time. The Bispectral Index (BIS) was used to maintain the same anaesthesia depth in all patients. The BIS value, the response to verbal stimuli and eye-opening time were used to assess recovery. After propofol discontinuation the BIS values returned to baseline in 11±4.2 min for Caucasians, in 12.5±5.1 min for Chinese, 15.9±6.3 min for Malays and 22.1±8.1 for Indians. Time to eye-opening was 11.63±4.2 min in Caucasians, 13.23±4.9 min in Chinese, 16.97±5.2 min in Malays and 22.3±6.6 min in Indians. The propofol consumption was significantly lower in Indians compared to the other three groups (P<0.01). The recovery of Indians was much slower compared to Chinese, Malays and Caucasians. The recovery time of Malays is significantly slower compared to Chinese and Caucasians. Differences in propofol consumption and recovery time were not significant between Chinese and Caucasians, but the ratio recovery time/propofol consumption was significantly lower in Caucasians compared to all the other groups.
Emergency Anaesthesia in a Patient with Gordon's Syndrome
Authors: Power G. E. , Hellier C. , Gordon R. D. 
Published: January 2019

Gordon's syndrome is a rare condition characterized by hypertension and hyperkalemia despite normal renal glomerular function. We report the administration of an anaesthetic to one such patient for an urgent surgical procedure. The patient's serum potassium was only marginally raised at the outset of the procedure. During surgery the serum potassium rose significantly, but responded to conventional management. Hyperkalaemia is a specific electrolyte disturbance that has numerous implications for the administration of an anaesthetic. Most importantly, there is a danger that further acute elevations may occur, caused by the surgery, the anaesthetic, or the condition itself.
High-dose Buprenorphine: Perioperative Precautions and Management Strategies
Authors: Roberts D. M. , Meyer-Witting M. 
Published: January 2019

Buprenorphine has been in clinical use in anaesthesia for several decades. Recently, the high-dose sublingual formulation (Subutex®, Reckitt Benckiser, Slough, U.K.) has been increasingly used as maintenance therapy in opioid dependence, as an alternative to methadone and other pharmacological therapies. Buprenorphine has unique pharmacological properties making it well suited for use as a maintenance therapy in opioid dependence. However, these same properties may cause difficulty in the perioperative management of pain. Buprenorphine is a partial opioid agonist, attenuating the effects of supplemental illicit or therapeutic opioid agonists. As a result of its high receptor affinity, supplemental opioids do not readily displace buprenorphine from the opioid receptor in standard doses. High-dose buprenorphine has an extended duration of action that prolongs both of these effects. The perioperative management of patients stabilized on high-dose buprenorphine and undergoing surgery requires consideration of the likely analgesic requirements. Where possible the buprenorphine should be continued. Pain management should focus on maximizing non-opioid analgesia, local anaesthesia and non-pharmacological techniques. Where pain may not be adequately relieved by these methods, the addition of a full opioid agonist such as fentanyl or morphine at appropriate doses should be considered, accompanied by close monitoring in a high dependency unit. In situations where this regimen is unlikely to be effective, preoperative conversion to morphine or methadone may be an option. Where available, liaison with a hospital-based alcohol and drug service should always be considered.
Growth of Staphylococcus epidermidis in Anaesthetic Resuscitative Drugs: Implications for Potential Contamination
Authors: Wu C. , Engler C. , Norton R. 
Published: January 2019

This controlled laboratory study investigated the survival of Staphylococcus epidermidis (S. epidermidis) over a 24 hour period in four commonly drawn-up anaesthetic resuscitative drugs: suxamethonium, atropine, metaraminol and ephedrine. These drugs were prepared in typical therapeutic concentrations and then inoculated with S. epidermidis. Samples of the inoculated drug preparations were cultured on horse blood agar plates at 0, 2, 6, 12 and 24 hourly intervals and incubated for 24 hours. Colony counts were performed at the end of the incubation period. Suxamethonium, atropine and metaraminol all showed an inhibitory effect on colony counts within the first six hours. There was a more gradual decline of colony counts over a 24 hour period in the ephedrine solution. This decline was similar to that occurring in the normal saline. It is concluded that suxamethonium, atropine and metaraminol do not support the survival of the common skin contaminant, S. epidermidis over a 24 hour period.
Unexpectedly High Block following Epidural Catheter Placement under Direct Vision: A Case Report
Authors: D'Agapeyeff A. , Crabb I. J. 
Published: January 2019

A 72-year-old female underwent elective lumbar spinal decompression. At the end of the procedure an epidural catheter was sited by the surgeon under direct vision. A bolus of levobupivacaine was injected. Shortly after reaching the recovery area, the patient collapsed and required re-intubation and mechanical ventilation. She was extubated five hours later and suffered no adverse sequelae. Having excluded other possible causes of immediate post-operative collapse, a clinical diagnosis of subdural blockade was made. A literature search using Medline has found no other case reports of such a complication following epidural placement under direct vision.