Predictive modelling for late rectal and urinary toxicities after prostate radiotherapy using planned and delivered dose.

BACKGROUND AND PURPOSE: Normal tissue complication probability (NTCP) parameters derived from traditional 3D plans may not be ideal in defining toxicity outcomes for modern radiotherapy techniques. This study aimed to derive parameters of the Lyman-Kutcher-Burman (LKB) NTCP model using prospectively scored clinical data for late gastrointestinal (GI) and genitourinary (GU) toxicities for high-risk prostate cancer patients treated using volumetric-modulated-arc-therapy (VMAT). Dose-volume-histograms (DVH) extracted from planned (DP) and accumulated dose (DA) were used. MATERIAL AND METHODS: DP and DA obtained from the DVH of 150 prostate cancer patients with pelvic-lymph-nodes irradiation treated using VMAT were used to generate LKB-NTCP parameters using maximum likelihood estimations. Defined GI and GU toxicities were recorded up to 3-years post RT follow-up. Model performance was measured using Hosmer-Lemeshow goodness of fit test and the mean area under the receiver operating characteristics curve (AUC). Bootstrapping method was used for internal validation. RESULTS: For mild-severe (Grade ≥1) GI toxicity, the model generated similar parameters based on DA and DP DVH data (DA-D50:71.6 Gy vs DP-D50:73.4; DA-m:0.17 vs DP-m:0.19 and DA/P-n 0.04). The 95% CI for DA-D50 was narrower and achieved an AUC of >0.6. For moderate-severe (Grade ≥2) GI toxicity, DA-D50 parameter was higher and had a narrower 95% CI (DA-D50:77.9 Gy, 95% CI:76.4-79.6 Gy vs DP-D50:74.6, 95% CI:69.1-85.4 Gy) with good model performance (AUC>0.7). For Grade ≥1 late GU toxicity, D50 and n parameters for DA and DP were similar (DA-D50: 58.8 Gy vs DP-D50: 59.5 Gy; DA-n: 0.21 vs DP-n: 0.19) with a low AUC of0.6. CONCLUSIONS: The achieved NTCP parameters using modern RT techniques and accounting for organ motion differs from QUANTEC reported parameters. DA-D50 of 77.9 Gy for GI and DA/DP-D50 of 81.7-81.9 Gy for GU demonstrated good predictability in determining the risk of Grade ≥2 toxicities especially for GI derived D50 and are recommended to incorporate as part of the DV planning constraints to guide dose escalation strategies while minimising the risk of toxicity

Adsorbate-induced reconstructions and nanostructures on high-index copper surfaces

High-index copper surfaces generally show a strong tendency to reconstruct, forming one- or even two-dimensional periodic nanostructures. In this paper, a survey will be presented of the various oxygen-induced reconstructions reported on high-index copper surfaces. In particular, the reconstructions of the Cu(210)-O system are presented, as revealed by low-energy electron diffraction (LEED) and scanning tunnelling microscopy (STM). The adsorption of oxygen leads to a series of (n X 1) (n = 4,3,2) surface reconstructions, the Cu(210)-(2 x 1)O structure being the most stable. Quantitative LEED analysis confirms an added row model comprising Cu-O-Cu rows along the [001] direction on the topmost layer with oxygen at the long bridge sites. A range of faceting behaviour and nanostructure formation is also observed for the Cu(210)-O and Cu(210)-Br systems, and compared with other high- and low-index Cu surfaces. Copyright (C) 2001 John Wiley & Sons

Molecular structure of the largemouth bass (Micropterus salmoides) Myf5 gene and its effect on skeletal muscle growth

Myogenic Regulatory Factors (MRFs), a family of basic helix-loop-helix (bHLH) transcription factors, play important roles in regulating skeletal muscle development and growth. Myf5, the primary factor of MRFs, initiates myogenesis. Its expression pattern during somitomyogenesis in some fish has been revealed. To further study its effect on fish muscle during postembryonic growth, characterization and function analysis of myf5 cDNA were carried out in largemouth bass. The 1,093 bp cDNA sequence was identified by RT-PCR and 3′RACE, then the ORF of Myf5 cDNA was cloned into the expression vector pcDNA3.1(−)/mycHisB. The recombinant plasmid pcDNA3.1(−)/mycHisB-Myf5 was injected into the dorsal muscle of tilapias. RT-PCR and histochemical results showed that the exogenous gene was transcribed and translated in vivo. Its effect on muscle growth focused on myofiber hypertrophy in white muscle 60 days post injection. This indicated that overexpression of Myf5 can promote myogenesis during the fish muscle postembryonic growth period

International expert consensus on the management of bleeding during VATS lung surgery

Intraoperative bleeding is the most crucial safety concern of video-assisted thoracic surgery (VATS) for a major pulmonary resection. Despite the advances in surgical techniques and devices, intraoperative bleeding is still not rare and remains the most common and potentially fatal cause of conversion from VATS to open thoracotomy. Therefore, to guide the clinical practice of VATS lung surgery, we proposed the International Interest Group on Bleeding during VATS Lung Surgery with 65 experts from 10 countries in the field to develop this consensus document. The consensus was developed based on the literature reports and expert experience from different countries. The causes and incidence of intraoperative bleeding were summarised first. Seven situations of intraoperative bleeding were collected based on clinical practice, including the bleeding from massive vessel injuries, bronchial arteries, vessel stumps, and bronchial stumps, lung parenchyma, lymph nodes, incisions, and the chest wall. The technical consensus for the management of intraoperative bleeding was achieved on these seven surgical situations by six rounds of repeated revision. Following expert consensus statements were achieved: (I) Bleeding from major vascular injuries: direct compression with suction, retracted lung, or rolled gauze is useful for bleeding control. The size and location of the vascular laceration are evaluated to decide whether the bleeding can be stopped by direct compression or by ligation. If suturing is needed, the suction-compressing angiorrhaphy technique (SCAT) is recommended. Timely conversion to thoracotomy with direct compression is required if the operator lacks experience in thoracoscopic angiorrhaphy. (II) Bronchial artery bleeding: pre-emptive clipping of bronchial artery before bronchial dissection or lymph node dissection can reduce the incidence of bleeding. Bronchial artery bleeding can be stopped by compression with the suction tip, followed by the handling of the vascular stump with energy devices or clips. (III) Bleeding from large vessel stumps and bronchial stumps: bronchial stump bleeding mostly comes from accompanying bronchial artery, which can be clipped for hemostasis. Compression for hemostasis is usually effective for bleeding at the vascular stump. Otherwise, additional use of hemostatic materials, re-staple or a suture may be necessary. (IV) Bleeding from the lung parenchyma: coagulation hemostasis is the first choice. For wounds with visible air leakage or an insufficient hemostatic effect of coagulation, suturing may be necessary. (V) Bleeding during lymph node dissection: non-grasping en-bloc lymph node dissection is recommended for the nourishing vessels of the lymph node are addressed first with this technique. If bleeding occurs at the site of lymph node dissection, energy devices can be used for hemostasis, sometimes in combination with hemostatic materials. (VI) Bleeding from chest wall incisions: the chest wall incision(s) should always be made along the upper edge of the rib(s), with good hemostasis layer by layer. Recheck the incision for hemostasis before closing the chest is recommended. (VII) Internal chest wall bleeding: it can usually be managed with electrocoagulation. For diffuse capillary bleeding with the undefined bleeding site, compression of the wound with gauze may be helpful

Differential transcriptomic profiles effected by oil palm phenolics indicate novel health outcomes

Abstract Background Plant phenolics are important nutritional antioxidants which could aid in overcoming chronic diseases such as cardiovascular disease and cancer, two leading causes of death in the world. The oil palm (Elaeis guineensis) is a rich source of water-soluble phenolics which have high antioxidant activities. This study aimed to identify the in vivo effects and molecular mechanisms involved in the biological activities of oil palm phenolics (OPP) during healthy states via microarray gene expression profiling, using mice supplemented with a normal diet as biological models. Results Having confirmed via histology, haematology and clinical biochemistry analyses that OPP is not toxic to mice, we further explored the gene expression changes caused by OPP through statistical and functional analyses using Illumina microarrays. OPP showed numerous biological activities in three major organs of mice, the liver, spleen and heart. In livers of mice given OPP, four lipid catabolism genes were up-regulated while five cholesterol biosynthesis genes were down-regulated, suggesting that OPP may play a role in reducing cardiovascular disease. OPP also up-regulated eighteen blood coagulation genes in spleens of mice. OPP elicited gene expression changes similar to the effects of caloric restriction in the hearts of mice supplemented with OPP. Microarray gene expression fold changes for six target genes in the three major organs tested were validated with real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and the correlation of fold changes obtained with these two techniques was high (R2 = 0.9653). Conclusions OPP showed non-toxicity and various pleiotropic effects in mice. This study implies the potential application of OPP as a valuable source of wellness nutraceuticals, and further suggests the molecular mechanisms as to how dietary phenolics work in vivo.</p

The distribution of the therapeutic monoclonal antibodies cetuximab and trastuzumab within solid tumors

<p><b>Abstract</b></p> <p>Background</p> <p>Poor distribution of some anticancer drugs in solid tumors may limit their anti-tumor activity.</p> <p>Methods</p> <p>Here we used immunohistochemistry to quantify the distribution of the therapeutic monoclonal antibodies cetuximab and trastuzumab in relation to blood vessels and to regions of hypoxia in human tumor xenografts. The antibodies were injected into mice implanted with human epidermoid carcinoma A431 or human breast carcinoma MDA-MB-231 transfected with <it>ERBB2 </it>(231-H2N) that express high levels of ErbB1 and ErbB2 respectively, or wild-type MDA-MB-231, which expresses intermediate levels of ErbB1 and low levels of ErbB2.</p> <p>Results</p> <p>The distribution of cetuximab in A431 xenografts and trastuzumab in 231-H2N xenografts was time and dose dependent. At early intervals after injection of 1 mg cetuximab into A431 xenografts, the concentration of cetuximab decreased with increasing distance from blood vessels, but became more uniformly distributed at later times; there remained however limited distribution and binding in hypoxic regions of tumors. Injection of lower doses of cetuximab led to heterogeneous distributions. Similar results were observed with trastuzumab in 231-H2N xenografts. In MDA-MB-231 xenografts, which express lower levels of ErbB1, homogeneity of distribution of cetuximab was achieved more rapidly.</p> <p>Conclusions</p> <p>Cetuximab and trastuzumab distribute slowly, but at higher doses achieve a relatively uniform distribution after about 24 hours, most likely due to their long half-lives in the circulation. There remains poor distribution within hypoxic regions of tumors.</p

Neural protection by naturopathic compounds—an example of tetramethylpyrazine from retina to brain

Given the advantages of being stable in the ambient environment, being permeable to the blood–brain and/or blood–eye barriers and being convenient for administration, naturopathic compounds have growingly become promising therapeutic candidates for neural protection. Extracted from one of the most common Chinese herbal medicines, tetramethylpyrazine (TMP), also designated as ligustrazine, has been suggested to be neuroprotective in the central nervous system as well as the peripheral nerve network. Although the detailed molecular mechanisms of its efficacy for neural protection are understood limitedly, accumulating evidence suggests that antioxidative stress, antagonism for calcium, and suppression of pro-inflammatory factors contribute significantly to its neuroprotection. In animal studies, systemic administration of TMP (subcutaneous injection, 50 mg/kg) significantly blocked neuronal degeneration in hippocampus as well as the other vulnerable regions in brains of Sprague–Dawley rats following kainate-induced prolonged seizures. Results from us and others also demonstrated potent neuroprotective efficacy of TMP for retinal cells and robust benefits for brain in Alzheimer’s disease or other brain injury. These results suggest a promising prospect for TMP to be used as a treatment of specific neurodegenerative diseases. Given the assessment of the distribution, metabolism, excretion, and toxicity information that is already available on most neuroprotective naturopathic compounds such as TMP, it would not take much preclinical data to justify bringing such therapeutic compounds to clinical trials in humans