Miracle-dz/UniFAR-FTUs huggingface dataset:
Minimizing morbidity in radiation oncology: a special issue from Future Oncology.

21st Century Oncology, 801 WH Smith Boulevard, Greenville, NC 27834, USA Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA, USA *Author for correspondence: rallison@rtsx.com This issue of Future Oncology highlights some of the accomplishments, limitations and promises of the field of Radiation Oncology, with a focus on means to minimize normal tissue toxicity. Today, more patients than ever who receive radiation therapy experience improved outcomes with lower morbidity than patients treated even a decade ago. This is due in large part to technological advances as outlined in the article by Allison et al. [1]. While the laws of physics that govern radiation therapy has not changed, the ability to accurately deliver tumoricidal doses to the cancer while also reducing dose to critical surrounding tissues has. The widespread use of imaging both during the development and delivery of a patient’s treatment has created a new level of treatment accuracy. Various forms of image-guided radiation therapy are currently used, with computed tomography-based most common. As detailed in this article, new forms of imaging including magnetic resonance and biologic approaches may soon come to the forefront, all with the promise of further limiting exposure and dose to normal tissues. Additionally, treatment delivery has simultaneously advanced allowing worldwide introduction of intensitymodulated radiation therapy to become the standard. When appropriate, this delivery technique allows for higher doses of radiation to be delivered to the tumor while simultaneously diminishing radiation dose to normal tissues. Another emerging treatment delivery technique is termed ‘radiosurgery. ’ With these tools, very large doses of radiation are delivered to relatively small volumes. This ideally minimizes normal tissue exposure and injury. With these new technologies may also come unintended consequences. A relatively unusual potential morbidity has been attributed to lung radiosurgery in which rib fracture or injury appears to be enhanced. In the article by Podder et al., the risk appears to be acceptable and the literature is reviewed [2]. The current state of the art of clinical outcomes for radiosurgery is highlighted by Mahadevan et al.’s report from the 2014 Radiosurgery Society Annual meeting [3]. The future of radiation therapy will also “Today, more patients than ever who receive radiation therapy experience improved outcomes with lower morbidity than patients treated even a decade ago. ”
Optical Coherence Tomography to Detect Epithelial Lesions of the Main Pancreatic Duct: An Ex Vivo Study

BACKGROUND:Optical coherence tomography (OCT) permits high-resolution, real-time, infrared-generated imaging of tissue microstructures by a probe inserted through the endoscope operative channel. Resolution is approximately 10 μm and the penetration depth of the near-focus probe is about 1 mm. The probe can be inserted into the main pancreatic duct (MPD) through a standard endoscopic retrograde cholangiopancreatography catheter.AIMS AND METHODS:To assess the ability of OCT to identify the structure of the MPD, to distinguish normal and malignant MPD epithelium, and to assess intra- and interobserver reproducibility of OCT images. Multiple sections of neoplastic and non-neoplastic segments of 10 consecutive surgical pancreatic specimens were obtained from patients with pancreatic head adenocarcinoma who had undergone Whipple resection, and repeated OCT radial and longitudinal scanning was done within 1 h of resection and before pathological examination. We compared 249 good-quality images with 100 histopathological sections.RESULTS:OCT recognized a definite, different pattern in 82.9% of tumor-free and in 97.6% of tumor-involved specimens; sensitivity and specificity for discrimination between adenocarcinoma and normal tissue were 78.6% and 88.9%, respectively. Inflammatory and dysplastic changes of the MPD showed an OCT pattern similar to that of the normal tissue in 53.3% of images. Overall, intraobserver reproducibility ranged from 85.1% to 100% and interobserver reproducibility ranged from 69.9% to 100% and from 89.7% to 100% for tumor-free and tumor-involved segments, respectively.CONCLUSIONS:OCT identified the neoplastic and non-neoplastic MPD layer structure and appeared to be a reproducible technique. In non-neoplastic conditions, OCT appeared unable to differentiate between normal and abnormal tissues in about half of the cases.
Impact of Co-occurring Mental Disorders and Chronic Physical Illnesses on Frequency of Emergency Department Use and Hospitalization for Mental Health Reasons

Background: Patients with mental disorders (MD) are at high risk for a wide range of chronic physical illnesses (CPI), often resulting in greater use of acute care services. This study estimated risk of emergency department (ED) use and hospitalization for mental health (MH) reasons among 678 patients with MD and CPI compared to 1,999 patients with MD only. Methods: Patients visiting one of six Quebec (Canada) ED for MH reasons and at onset of a MD in 2014–15 (index year) were included. Negative binomial models comparing the two groups estimated risk of ED use and hospitalization at 12-month follow-up to index ED visit, controlling for clinical, sociodemographic, and service use variables. Results: Patients with MD, more severe overall clinical conditions and those who received more intensive specialized MH care had higher risks of frequent ED use and hospitalization. Continuity of medical care protected against both ED use and hospitalization, while general practitioner (GP) consultations protected against hospitalization only. Patients aged 65+ had lower risk of ED use, whereas risk of hospitalization was higher for the 45–64- vs. 12–24-year age groups, and for men vs. women. Conclusion: Strategies including assertive community treatment, intensive case management, integrated co-occurring treatment, home treatment, and shared care may improve adequacy of care for patients with MD-CPI, as well as those with MD only whose clinical profiles were severe. Prevention and outreach strategies may also be promoted, especially among men and older age groups.
Tumor Necrosis Factor‐Alpha, Interleukin‐6, and Interleukin‐10 Levels are Altered in Preeclampsia: A Systematic Review and Meta‐Analysis

Published reports testing the association between cytokine levels and preeclampsia are conflicting. This comprehensive systematic review and meta‐analysis aimed at testing the association between preeclampsia and maternal circulating tumor necrosis factor‐alpha (TNF‐α), interleukin (IL)‐6, and IL‐10.
[Trastuzumab in combination with chemotherapy versus chemotherapy alone for first-line treatment of HER2-positive advanced gastric or gastroesophageal junction cancer: a Phase III, multi-center, randomized controlled trial, Chinese subreport].

OBJECTIVE To evaluate the efficacy and safety of trastuzumab in combination with chemotherapy versus chemotherapy alone in the first-line treatment of HER-2-positive advanced gastric or gastro-oesophageal junction cancer. METHODS Fifteen Chinese research centers are involved in the BO18255 (ToGA) study. Patients with gastric or gastro-oesophageal junction cancer were eligible for inclusion if their tumor showed overexpression of HER-2 protein by immunohistochemistry +++ or FISH-positive. Patients were randomly assigned in a 1:1 ratio to receive a chemotherapy regimen consisting of capecitabine or 5-FU plus cisplatin or chemotherapy in combination with intravenous trastuzumab. The primary endpoint was overall survival. RESULTS Eighty-five Chinese patients were enrolled in this study, of whom 84 were included in the primary analysis: trastuzumab plus chemotherapy (FP/H) (n = 36) and chemotherapy alone (FP)(n = 48). The median follow-up was 15.2 months in the FP/H group and 14.2 months in the FP group. The median survival time was 12.6 months in the FP/H group compared with 9.7 months in the FP group [hazard ratio 0.72, 95%CI (0.40; 1.29)]. Grade 3/4 adverse events were higher in the FP/H(63.9%)than FP (47.9%) groups, including neutropenia, vomiting and nausea. Two mild cardiac adverse events occurred in the FP/H group. Severe adverse events occurred in 3 cases of both two groups, respectively. CONCLUSIONS Addition of trastuzumab to chemotherapy is well tolerated and shows improved survival in Chinese patients with advanced gastric or gastro-oesophageal junction cancer. These results are consistent with the results of ToGA whole population trial. Trastuzumab in combination with chemotherapy can be considered as a new option for patients with HER-2-positive advanced gastric or gastro-oesophageal junction cancer.
Initial Preclinical Evaluation of 18F-Fluorodeoxysorbitol PET as a Novel Functional Renal Imaging Agent

Accurate assessment of kidney function plays an essential role for optimal clinical decision making in a variety of diseases. The major intrinsic advantages of PET are superior spatial and temporal resolutions for quantitative tomographic renal imaging. 2-deoxy-2-18F-fluorodeoxysorbitol (18F-FDS) is an analog of sorbitol that is reported to be freely filtered at the renal glomerulus without reabsorption at the tubule. Furthermore, it can be synthesized via simple reduction of widely available 18F-FDG. We tested the feasibility of 18F-FDS renal PET imaging in rats. Methods: The systemic and renal distribution of 18F-FDS were determined by dynamic 35-min PET imaging (15 frames × 8 s, 26 frames × 30 s, 20 frames × 60 s) with a dedicated small-animal PET system and postmortem tissue counting in healthy rats. Distribution of coinjected 99mTc-diethylenetriaminepentaacetic acid (DTPA) was also estimated as a reference. Plasma binding and in vivo stability of 18F-FDS were determined. Results: In vivo PET imaging visualized rapid excretion of the administrated 18F-FDS from both kidneys, with minimal tracer accumulation in other organs. Initial cortical tracer uptake followed by visualization of the collecting system could be observed with high contrast. Split-function renography curves were successfully obtained in healthy rats (the time of maximal concentration [Tmax] right [R] = 2.8 ± 1.2 min, Tmax left [L] = 2.9 ± 1.5 min, the time of half maximal concentration [T1/2max] R = 8.8 ± 3.7 min, T1/2max L = 11.1 ± 4.9 min). Postmortem tissue counting of 18F-FDS confirmed the high kidney extraction (kidney activities at 10, 30, and 60 min after tracer injection [percentage injected dose per gram]: 1.8 ± 0.7, 1.2 ± 0.1, and 0.5 ± 0.2, respectively) in a degree comparable to 99mTc-DTPA (2.5 ± 1.0, 1.5 ± 0.2, and 0.8 ± 0.3, respectively). Plasma protein binding of 18F-FDS was low (<0.1%), and metabolic transformation was not detected in serum and urine. Conclusion: In rat experiments, 18F-FDS demonstrated high kidney extraction and excretion, low plasma protein binding, and high metabolic stability as preferable properties for renal imaging. These preliminary results warrant further confirmatory studies in large animal models and clinical studies as a novel functional renal imaging agent, given the advantages of PET technology and broad tracer availability.
Reliability of scores from physical activity monitors in adults with multiple sclerosis.

We examined the reliability of scores from physical activity monitors in a sample of 193 individuals with multiple sclerosis (MS) who wore a pedometer and an accelerometer for a 7-day period. There were no significant differences among days for the pedometer (p = .12) or the accelerometer (p = .15) indicating that week and weekend days can be analyzed in a single intra-class correlation (ICC) analytic model. The 7 days of monitoring yielded ICC estimates of . 93 for both the pedometer and accelerometer, and a minimum of 3 days yielded a reliability of . 80 for both the pedometer and accelerometer. Results indicated that physical activity monitor scores are reliable measures of physical activity for individuals with MS.
Loss of Heterozygosity Combined with Promoter Hypermethylation, the Main Mechanism of Human MutL Homolog (hMLH1) Gene Inactivation in Non-Small Cell Lung Cancer in a Chinese Population

Aims and background The mechanism of human MutL Homolog (hMLH1) gene transcriptional inactivation in non-small cell lung cancer (NSCLC) is still unclear. The aim of this study is to further investigate the main mechanism of hMLH1 gene inactivation in NSCLC samples of Chinese patients. Methods and study design This study was performed in surgically resected primary tumor and matched normal tissues from 116 NSCLC cases. The hMLH1 gene alterations examined included loss of heterozygosity (LOH) by D3S1612 locus PCR-electrophoresis-silver staining and promoter methylation by HpaII/ MspI-based PCR analysis. Loss of hMLH1 mRNA expression was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and loss of hMLH1 protein expression was studied by immunohistochemistry and Western blot. Results The frequencies of LOH and promoter hypermethylation of the hMLH1 gene were 68.1% (79/116) and 72.4% (84/116), respectively. Among the 79 hMLH1 LOH (+) cases, 68 (86.1%) showed hypermethylation, which was significantly higher than in the LOH (–) group. The frequencies of loss of hMLH1 mRNA expression and protein expression in NSCLC were 79.3% (92/116) and 76.7% (89/116), respectively. The frequency of 2-hit inactivation of hMLH1, 75.3% (67/89), by LOH combined with promoter hypermethylation was related to the loss of protein expression. Conclusions Biallelic inactivation of the hMLH1 gene by LOH combined with promoter hypermethylation is likely to cause inactivation of hMLH1 protein and to play an important role in the development of NSCLC in the Chinese population.
Drug-Metabolizing Enzymes, Polymorphisms and Interindividual Response to Environmental Toxicants

Abstract Individual risk of toxicity or cancer reflects the amount of exposure to environmental agents, combined with one's underlying genetic predisposition. More than six dozen human ecogenetic polymorphisms have been described; whereas some of these have been demonstrated to be associated with altered risks of toxicity or cancer, others presently remain equivocal and require further study. Thus, genetic differences in the regulation, expression and activity of “environmental susceptibility genes” can be decisive in defining susceptibility to toxicity or cancer. “Drug-metabolizing enzymes” (DMEs) are regarded as one class of environmental susceptibility genes. DME genes have actually existed on this planet for more than 2.5 billion years, and might more appropriately be named “effector-metabolizing enzymes. ” Receptors controlling DME levels have been called “DME receptors. ” DMEs have functioned in many critical life processes in prokaryotes and, more recently, in countless basic functions in plants and animals—events that evolved long before the existence of pharmaceutical companies and apothecaries. DME genes exist in every eukaryotic cell and probably in all prokaryotes. Virtually all environmental agents act as either agonists or antagonists—in competing with endogenous ligands that bind to DME receptors and/or competing as substrates for the DMEs. Over the past decade it has become clear that each of us has our own “individual fingerprint” of unique alleles coding for DMEs. The underlying genetic predisposition of each patient will reflect combinations of poor- and extensive-metabolizer phenotypes; if these enzymes cooperate in the same metabolic pathway for any given drug or environmental agent, such ecogenetic variability might be synergistic and lead to as much as 30- or >40-fold differences in activation or degradation. The end result can be large interindividual differences in risk of environmentally caused toxicity or cancer.
Design of thermal process controller by using Bodé plots of open loop frequency characteristics

The literature, dealing with automatic control systems, describes the application of Bodé plots of open loop frequency characteristics to the controller parameter synthesis as the trial and error method. The procedure suggested is the one for controller parameter determining according to the given phase margin of the open-loop system frequency characteristics. The procedure is repeated until the required closed-loop response overshoot determined by means of the computer simulation is achieved.
Effects of Phytic Acid-Degrading Bacteria on Mineral Element Content in Mice

Trace minerals are extremely important for balanced nutrition, growth, and development in animals and humans. Phytic acid chelation promotes the use of probiotics in nutrition. The phytic acid-degrading strain Lactococcus lactis psm16 was obtained from swine milk by enrichment culture and direct plate methods. In this study, we evaluated the effect of the strain psm16 on mineral element content in a mouse model. Mice were divided into four groups: basal diet, 1% phytic acid, 1% phytic acid + psm16, 1% phytic acid + 500 U/kg commercial phytase. Concentrations of acetic acid, propionic acid, butyric acid, and total short-chain fatty acids were significantly increased in the strain psm16 group compared to the phytic acid group. The concentrations of copper (p = 0.021) and zinc (p = 0.017) in liver, calcium (p = 0.000), manganese (p = 0.000), and zinc (p = 0.000) in plasma and manganese (p = 0.010) and zinc (p = 0.022) in kidney were significantly increased in psm16 group, while copper (p = 0.007) and magnesium (p = 0.001) were significantly reduced. In conclusion, the addition of phytic acid-degrading bacteria psm16 into a diet including phytic acid can affect the content of trace elements in the liver, kidney, and plasma of mice, counteracting the harmful effects of phytic acid.
Suppressor of Cytokine Signaling 1 (SOCS-1) and SOCS-3 Cause Insulin Resistance through Inhibition of Tyrosine Phosphorylation of Insulin Receptor Substrate Proteins by Discrete Mechanisms

ABSTRACT Insulin resistance is a pathophysiological component of type 2 diabetes and obesity and also occurs in states of stress, infection, and inflammation associated with an upregulation of cytokines. Here we show that in both obesity and lipopolysaccharide (LPS)-induced endotoxemia there is an increase in suppressor of cytokine signaling (SOCS) proteins, SOCS-1 and SOCS-3, in liver, muscle, and, to a lesser extent, fat. In concordance with these increases by LPS, tyrosine phosphorylation of the insulin receptor (IR) is partially impaired and phosphorylation of the insulin receptor substrate (IRS) proteins is almost completely suppressed. Direct overexpression of SOCS-3 in liver by adenoviral-mediated gene transfer markedly decreases tyrosine phosphorylation of both IRS-1 and IRS-2, while SOCS-1 overexpression preferentially inhibits IRS-2 phosphorylation. Neither affects IR phosphorylation, although both SOCS-1 and SOCS-3 bind to the insulin receptor in vivo in an insulin-dependent fashion. Experiments with cultured cells expressing mutant insulin receptors reveal that SOCS-3 binds to Tyr960 of IR, a key residue for the recognition of IRS-1 and IRS-2, whereas SOCS-1 binds to the domain in the catalytic loop essential for IRS-2 recognition in vitro. Moreover, overexpression of either SOCS-1 or SOCS-3 attenuates insulin-induced glycogen synthesis in L6 myotubes and activation of glucose uptake in 3T3L1 adipocytes. By contrast, a reduction of SOCS-1 or SOCS-3 by antisense treatment partially restores tumor necrosis factor alpha-induced downregulation of tyrosine phosphorylation of IRS proteins in 3T3L1 adipocytes. These data indicate that SOCS-1 and SOCS-3 act as negative regulators in insulin signaling and serve as one of the missing links between insulin resistance and cytokine signaling.
Using program slicing to assist in the detection of equivalent mutants

While mutation testing has proved to be an effective way of finding software faults, currently it is only applied to relatively small programs. One of the main reasons for this is the human analysis required in detecting equivalent mutants. Here program slicing is used to simplify this problem. Progam slicing is also used to reduce the number of equivalent mutants produced. Copyright © 1999 John Wiley & Sons, Ltd.
Prevalence and incidence

A randomised controlled trial investigated whether screening and treating women for chlamydial infection reduced the subsequent occurrence of pelvic inflammatory disease.1 Between 2004 and 2006, vaginal swabs were provided by 2529 sexually active female students. The samples were randomly allocated to immediate testing (screening group), or storage and deferred screening after a year (control group). After screening, treatment for chlamydial infection was offered to women where necessary. All women were able to undertake independent testing for chlamydia during the follow-up period of one year. At baseline, 5.4% of the women in the screened group tested positive for chlamydia compared to 5.9% of the controls. Over the following twelve months, 1.3% of the screened women developed pelvic inflammatory disease compared with 1.9% of the controls. Which of the following statements, if any, are true?
Metabolism of apigenin by rat liver phase I and phase ii enzymes and by isolated perfused rat liver.

The metabolism of apigenin, a low estrogenic flavonoid phytochemical, was investigated in rat using liver models both in vitro (subcellular fractions) and ex vivo (isolated perfused liver). In vitro, phase I metabolism led to the formation of three monohydroxylated derivatives: luteolin which was the major metabolite (K(m) = 22.5 +/- 1.5 microM; V(max) = 5.605 +/- 0.090 nmol/min/mg protein, means +/- S.E. M. ), scutellarein, and iso-scutellarein. These oxidative pathways were mediated by cytochrome P450 monooxygenases (P450s). The use of P450 inhibitors and inducers showed that CYP1A1, CYP2B, and CYP2E1 are involved. In vitro studies of phase II metabolism indicated that apigenin underwent conjugation giving three monoglucuronoconjugates and one monosulfoconjugate. Luteolin led to the formation of four monoglucuronoconjugates, two sulfoconjugates, and one methylconjugate identified as diosmetin. Ex vivo during the apigenin perfusion of an isolated rat liver, none of the phase I metabolites could be recovered. In contrast, two monoglucuronoconjugates and one of the sulfoconjugates of apigenin already identified in vitro were recovered. Moreover, two new derivatives were isolated and identified as a diglucuronoconjugate and a glucuronosulfoconjugate. This work provides new data about the metabolism of apigenin and shows the interest value of using various experimental models in metabolic studies.