Objectives
To evaluate our clinical experience with percutaneous image‐guided radiofrequency ablation (RFA) of 200 renal tumours in a large tertiary referral university institution.
Patients and ...Methods
Image‐guided RFA (ultrasonography or computed tomography CT) of 200 renal tumours in 165 patients from June 2004 to 2012 was prospectively evaluated. Institutional Review Board approval was granted.
The treatment response and technical success were defined by absence of contrast enhancement within the tumour on contrast enhanced CT or magnetic resonance imaging.
Both major and minor complications, glomerular filtration rate (GFR) before and after RFA, the management and outcomes of the complications, as well as oncological outcome were prospectively documented.
Multivariate analysis was used to determine variables associated with major complications and also the percentage GFR change after RFA.
The overall (OS), 5‐year cancer‐specific (CSS), local recurrence‐free (LRFS) and metastasis‐free survival (MFS) rates are presented using the Kaplan–Meier curves.
Results
In all, 200 tumours were RF ablated with a mean (range) tumour size of 2.9 (1–5.6) cm and the mean (range) patient age was 67.7 (21–88.6) years with a mean follow‐up period of 46.1 months. The primary technical and overall technical success rate was 95.5% and 98.5%, respectively. Two independent predictors of successful RFA in a single sitting were tumour size (<3 cm) and exophytic location in multivariate logistic regression analysis.
Major complications included ureteric injury (six patients), calyceal‐cutaneous fistula (one), acute tubular necrosis (one) and abscess (two). Two independent predictors of ureteric injury were central location and lower pole position.
Within this cohort of patients, only four patients developed significant renal function deterioration i.e. >25% decreased in GFR. In all, 161 (98%) patients of the 165 patients have preservation of renal function. Any change in renal function after RFA was not influenced by tumour factors or solitary kidney status.
In our clinical series, this yielded a 5‐year OS, CSS, LRFS and MFS rates of 75.8%, 97.9%, 93.5% and 87.7% respectively.
Conclusions
Image‐guided RFA is a safe, nephron sparing and effective treatment for small renal cell carcinoma (RCC) tumours with a low rate of recurrence and has good 5‐year CSS and MFS rates.
DNA interstrand crosslinks (ICLs) are extremely cytotoxic, but the mechanism of their repair remains incompletely understood. Using Xenopus egg extracts, we previously showed that repair of a ...cisplatin ICL is triggered when two replication forks converge on the lesion. After CDC45/MCM2-7/GINS (CMG) ubiquitylation and unloading by the p97 segregase, FANCI-FANCD2 promotes DNA incisions by XPF-ERCC1, leading to ICL unhooking. Here, we report that, during this cell-free ICL repair reaction, one of the two converged forks undergoes reversal. Fork reversal fails when CMG unloading is inhibited, but it does not require FANCI-FANCD2. After one fork has undergone reversal, the opposing fork that still abuts the ICL undergoes incisions. Our data show that replication fork reversal at an ICL requires replisome disassembly. We present a revised model of ICL repair that involves a reversed fork intermediate.
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•Replication forks undergo reversal during repair of a defined DNA interstrand crosslink•Fork reversal requires replicative CMG helicase unloading•DNA incisions occur in the context of a single fork
DNA interstrand crosslinks (ICLs) are extremely cytotoxic lesions that are mainly repaired in a replication-coupled manner. Using a cell-free system, Amunugama et al. report that, during ICL repair, replication forks undergo reversal. Fork reversal requires replicative CMG helicase unloading.
Chloroquine remains the mainstay of treatment for Plasmodium vivax malaria despite increasing reports of treatment failure. We did a systematic review and meta-analysis to investigate the effect of ...chloroquine dose and the addition of primaquine on the risk of recurrent vivax malaria across different settings.
A systematic review done in MEDLINE, Web of Science, Embase, and Cochrane Database of Systematic Reviews identified P vivax clinical trials published between Jan 1, 2000, and March 22, 2017. Principal investigators were invited to share individual patient data, which were pooled using standardised methods. Cox regression analyses with random effects for study site were used to investigate the roles of chloroquine dose and primaquine use on rate of recurrence between day 7 and day 42 (primary outcome). The review protocol is registered in PROSPERO, number CRD42016053310.
Of 134 identified chloroquine studies, 37 studies (from 17 countries) and 5240 patients were included. 2990 patients were treated with chloroquine alone, of whom 1041 (34·8%) received a dose below the target 25 mg/kg. The risk of recurrence was 32·4% (95% CI 29·8–35·1) by day 42. After controlling for confounders, a 5 mg/kg higher chloroquine dose reduced the rate of recurrence overall (adjusted hazard ratio AHR 0·82, 95% CI 0·69–0·97; p=0·021) and in children younger than 5 years (0·59, 0·41–0·86; p=0·0058). Adding primaquine reduced the risk of recurrence to 4·9% (95% CI 3·1–7·7) by day 42, which is lower than with chloroquine alone (AHR 0·10, 0·05–0·17; p<0·0001).
Chloroquine is commonly under-dosed in the treatment of vivax malaria. Increasing the recommended dose to 30 mg/kg in children younger than 5 years could reduce substantially the risk of early recurrence when primaquine is not given. Radical cure with primaquine was highly effective in preventing early recurrence and may also improve blood schizontocidal efficacy against chloroquine-resistant P vivax.
Wellcome Trust, Australian National Health and Medical Research Council, and Bill & Melinda Gates Foundation.
The rhizosphere differs from the bulk soil in a range of biochemical, chemical and physical processes that occur as a consequence of root growth, water and nutrient uptake, respiration and ...rhizodeposition. These processes also affect microbial ecology and plant physiology to a considerable extent. This review concentrates on two features of this unique environment: rhizosphere geometry and heterogeneity in both space and time. Although it is often depicted as a soil cylinder of a given radius around the root, drawing a boundary between the rhizosphere and bulk soil is an impossible task because rhizosphere processes result in gradients of different sizes. For instance, because of diffusional constraints, root uptake can result in a depletion zone extending <1 mm for phosphate to several centimetres for nitrate, while respiration may affect the bulk of the soil. Rhizosphere processes are responsible for spatial and temporal heterogeneities in the soil, although these are sometimes difficult to distinguish from intrinsic soil heterogeneity. A further complexity is that these processes are regulated by plants, microbial communities and soil constituents, and their many interactions. Novel in situ techniques and modelling will help in providing a holistic view of rhizosphere functioning, which is a prerequisite for its management and manipulation.
Our preliminary studies identified a small population side population (SP) cells in pancreatic cancer cells with stem cell-like properties, which were able to induce fast and aggressive tumor ...formation in nude mice. Gene expression analysis showed a significant difference in the expression of more than 1,300 genes in SP cells, among which a highly significant difference in microRNA expression of miR-21 and miR-221 between SP and NSP cells was identified. SP cells were identified and characterized by flow cytometry using Hoechst 33342 dye staining from a highly metastatic human pancreatic cancer cell line (L3.6pl). Antagomir transfection was performed using miRNA-21 and miRNA-221 antisense oligonucleotides (ASOs) and followed by detection of cell apoptosis, cell cycle progression, chemosensitivity, and invasion. Sorted SP cells from gemcitabine-resistant L3.6pl cells (L3.6pl
Gres
-SP) cells were orthotopically implanted in nude mice with or without miRNA-21 and miRNA-221 ASOs mono- and combination therapy. The administration of antagomir-21 and antagomir-221 significantly reduced the SP cell fraction, decreased SP cell differentiation, and downstream gene regulation, and thereby induced reduction of L3.6pl cell proliferation, invasion, and chemoresistance against gemcitabine and 5-Fluorouracil. Combination of ASOs therapy against miRNA-21 and miRNA-221 significantly inhibited primary tumor growth and metastasis compared to single antagomir treatment, especially, in L3.6pl
Gres
-SP-induced pancreatic tumor growth in vivo. These findings further indicate that the inhibition of miR-21 and miR-221 appear particularly suitable to target stem-like subpopulations and address their specific biological function to promote tumor progression in pancreatic cancer.
•The field of NIBS is expanding and adequate training for all NIBS practitioners is needed.•Training should be matched to the responsibilities of Technicians, Clinicians, and Scientists.•We define ...competencies and propose curricula for TMS and tES organized in Core knowledge, Safety/ethics, Basic Skills, and Advanced Skills.
As the field of noninvasive brain stimulation (NIBS) expands, there is a growing need for comprehensive guidelines on training practitioners in the safe and effective administration of NIBS techniques in their various research and clinical applications. This article provides recommendations on the structure and content of this training. Three different types of practitioners are considered (Technicians, Clinicians, and Scientists), to attempt to cover the range of education and responsibilities of practitioners in NIBS from the laboratory to the clinic. Basic or core competencies and more advanced knowledge and skills are discussed, and recommendations offered regarding didactic and practical curricular components. We encourage individual licensing and governing bodies to implement these guidelines.
Many employees in modern, knowledge-based organizations are concurrently involved in more than one team at the same time. This study investigated whether a within-person change in such individual ...multiple team membership (MTM) may precede and may be predicted by changes in an employee’s overall job performance. We examined this reciprocal relationship using longitudinal archival data from a large knowledge-intensive organization, comprising 1,875 employees and spanning 5 consecutive years. A latent change score model demonstrated that an increase in an employee’s MTM was associated with a subsequent decrease in his or her overall job performance evaluations. By contrast, an increase in job performance was associated with a subsequent increase in an employee’s MTM. Moreover, our results indicated that although an increase in an individual employee’s MTM initially decreases his or her job performance, in the long run, this increase in MTM was associated with higher job performance. Together, these results suggest a dynamic association between an individual employee’s MTM and his or her overall job performance, such that these variables are mutually connected in a highly complex manner over time.
Intervertebral disc (IVD) degeneration is an important contributor to the development of back pain, and a key factor relating pain and degeneration are the presence of pro-inflammatory cytokines and ...IVD motion. There is surprisingly limited understanding of how mechanics and inflammation interact in the IVD. This study investigated interactions between mechanical loading and pro-inflammatory cytokines in a large animal organ culture model to address fundamental questions regarding (i.) how inflammatory mediators arise within the IVD, (ii.) how long inflammatory mediators persist, and (iii.) how inflammatory mediators influence IVD biomechanics.
Bovine caudal IVDs were cultured for 6 or 20-days under static & dynamic loading with or without exogenous TNFα in the culture medium, simulating a consequence of inflammation of the surrounding spinal tissues. TNFα transport within the IVD was assessed via immunohistochemistry. Changes in IVD structural integrity (dimensions, histology & aggrecan degradation), biomechanical behavior (Creep, Recovery & Dynamic stiffness) and pro-inflammatory cytokines in the culture medium (ELISA) were assessed.
TNFα was able to penetrate intact IVDs when subjected to dynamic loading but not static loading. Once transported within the IVD, pro-inflammatory mediators persisted for 4-8 days after TNFα removal. TNFα exposure induced changes in IVD biomechanics (reduced diurnal displacements & increased dynamic stiffness).
This study demonstrated that exposure to TNFα, as might occur from injured surrounding tissues, can penetrate healthy intact IVDs, induce expression of additional pro-inflammatory cytokines and alter IVD mechanical behavior. We conclude that exposure to pro-inflammatory cytokine may be an initiating event in the progression of IVD degeneration in addition to being a consequence of disease.
The treatment of patients with haematological malignancies by means of haematopoietic stem cell transplantation (HSCT) is often accompanied by life threatening infections. With emerging antimicrobial ...resistance there is an increased need for new agents, with a beneficial safety profile. Therefore we evaluated the safety of the promising new antimicrobial peptide human lactoferrrin 1-11 (hLF1-11) in healthy volunteers and patients.
We undertook a sequential, randomised, double-blind, placebo-controlled study using ascending single (0.005, 0.05, 0.5, 5 mg) and multiple intravenous doses (0.5, 5 mg) in healthy volunteers, and open-label, single intravenous 5 mg doses in autologous HSCT recipients.
Single and multiple doses of hLF1-11 were tolerable up to 5 mg intravenously in healthy volunteers, while 5 mg single dose was tolerable in patients. Elevations in transaminases possibly related to treatment were reversible and not serious.
The new antimicrobial hLF1-11 is well tolerated in healthy volunteers with repeated daily doses up to 5 mg. The side-effect profile is very favourable for an antimicrobial, the only undesirable effect being a possible elevation of transaminases, which may be related to hLF1-11 although the current data do not allow conclusive interpretation of treatment relationship. A lower dose is recommended for the forthcoming multiple dosing studies in HSCT patients.
ClinicalTrials.gov: nct00509938.
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