Evaluation and evolution of apparent diffusion coefficient (ADC) in image-guided adaptive brachytherapy (IGABT) for cervical cancer

PURPOSEImage-guided adaptive brachytherapy (IGABT) recently has shown excellent clinical outcomes with superior local control and less toxicity. For IGABT, T2W (T2-weighted) MRI is the gold standard. However, studies have shown that target delineation with the same results in uncertainties, poor interobserver variabilities, and low conformity indices for high-risk clinical target volume contours. In this study, we investigate the role of diffusion-weighted imaging–derived apparent diffusion coefficient (ADC) maps to aid in IGABT. We also evaluated ADC from the baseline to brachytherapy.Methods and MaterialsThirty selected patients were enrolled for this study, and two MRIs were taken at diagnosis and before brachytherapy. Patients were divided into two groups, Group 1 being patients with parametrial involvement before external beam radiotherapy and no parametrial involvement before brachytherapy. Group 2 included patients with parametrial involvement before external beam radiotherapy and persistent parametrial involvement before brachytherapy. ADC was measured at the center, edge, and 1 cm from the edge.ResultsThe measured ADC increased from diagnosis to brachytherapy, and this increase was more for the patients in Group 1 than in Group 2. The mean TDadc (diagnosis ADC, center), TEadc (tumor edge ADC diagnosis), and T1cmDadc (1 cm from edge at diagnosis) were 0.884, 1.45, and 1.9 × 10^?3 mm²/s, respectively. The TBadc (ADC at brachytherapy, center), TEBadc (tumor edge ADC at brachytherapy), and TE1cmBadc (1 cm from edge brachytherapy) were 1.2, 1.8, and 2.3 × 10^?3 mm²/s, respectively, p-value <0.00001. No abnormal ADC was present outside the high-risk clinical target volume contours.ConclusionMRI-based IGABT using T2W imaging essentially covers all functionally abnormal zones at brachytherapy. Diffusion-weighted imaging, along with ADC maps, should only be used as a supplement for target delineation.     

Retrograde Mitochondrial Transport Is Essential for Organelle Distribution and Health in Zebrafish Neurons

In neurons, mitochondria are transported by molecular motors throughout the cell to form and maintain functional neural connections. These organelles have many critical functions in neurons and are of high interest as their dysfunction is associated with disease. While the mechanics and impact of anterograde mitochondrial movement toward axon terminals are beginning to be understood, the frequency and function of retrograde (cell body directed) mitochondrial transport in neurons are still largely unexplored. While existing evidence indicates that some mitochondria are retrogradely transported for degradation in the cell body, the precise impact of disrupting retrograde transport on the organelles and the axon was unknown. Using long-term, in vivo imaging, we examined mitochondrial motility in zebrafish sensory and motor axons. We show that retrograde transport of mitochondria from axon terminals allows replacement of the axon terminal population within a day. By tracking these organelles, we show that not all mitochondria that leave the axon terminal are degraded; rather, they persist over several days. Disrupting retrograde mitochondrial flux in neurons leads to accumulation of aged organelles in axon terminals and loss of cell body mitochondria. Assays of neural circuit activity demonstrated that disrupting mitochondrial transport and function has no effect on sensory axon terminal activity but does negatively impact motor neuron axons. Taken together, our work supports a previously unappreciated role for retrograde mitochondrial transport in the maintenance of a homeostatic distribution of mitochondria in neurons and illustrates the downstream effects of disrupting this process on sensory and motor circuits.SIGNIFICANCE STATEMENT Disrupted mitochondrial transport has been linked to neurodegenerative disease. Retrograde transport of this organelle has been implicated in turnover of aged organelles through lysosomal degradation in the cell body. Consistent with this, we provide evidence that retrograde mitochondrial transport is important for removing aged organelles from axons; however, we show that these organelles are not solely degraded, rather they persist in neurons for days. Disrupting retrograde mitochondrial transport impacts the homeostatic distribution of mitochondria throughout the neuron and the function of motor, but not sensory, axon synapses. Together, our work shows the conserved reliance on retrograde mitochondrial transport for maintaining a healthy mitochondrial pool in neurons and illustrates the disparate effects of disrupting this process on sensory versus motor circuits.     

To study the clinical efficacy and nephrotoxicity along with the risk factors for acute kidney injury associated with parenteral polymyxin B

Aim:

The aim of this study was to evaluate the clinical efficacy and nephrotoxicity along with the risk factors for acute kidney injury (AKI) associated with the parenteral polymyxin B in patients with the multidrug resistance (MDR) gram −ve infections in a tertiary Intensive care unit (ICU).

Materials and Methods:

A retrospective cohort study (March 2010-October 2011) was conducted in Medical ICU of a 23 bedded tertiary care hospital in Northern India.

Results:

Out of 71 ICU patients who were administered polymyxin B, only 32 (M:F = 1:0.8) met the inclusion criteria. Patients with concurrent administration of nephrotoxic drugs were excluded from the study. Mean age of patients was 48.53 ± 13.90 years ranging from 16 years to 68 years. 6 out of 32 (18.7%) patients progressed to AKI, whereas renal functions remained normal in 26 (81.2%) patients. No statistically significant difference was observed in mortality between AKI and non AKI patients at the end of therapy (33.3% vs. 26.9%, P value 0.756). Older age (62.33 ± 11.90 vs. 45.34 ± 2.45, P value 0.005) was found to be an independent risk factor for causing nephrotoxicity.

Conclusion:

In the present scenario of rising infections with MDR gram −ve micro-organisms, this pilot study suggests that polymyxin B can be used effectively and safely in patients not receiving other nephrotoxic drugs, with cautious administration in older patients as they are more vulnerable to nephrotoxicity caused by polymyxin B.     

A new begomovirus–betasatellite complex is associated with chilli leaf curl disease in Sri Lanka

Leaf curl disease of chilli (LCDC) is a major constraint in production of chilli in the Indian subcontinent. The objective of this study was to identify the begomovirus species occurring in chilli in Sri Lanka, where the LCDC was initially recorded in 1938. The virus samples were collected from the North Central Province, the major chilli growing region in Sri Lanka with a history of epidemic prevalence of LCDC. The virus could be readily transmitted by Bemisia tabaci to chilli, tomato and tobacco, where vein clearing followed by leaf curl developed. The genome analysis of two isolates obtained from two distantly located fields showing 100 % LCDC, revealed that the DNA-A genome (2754 nucleotides) shared 89.5 % sequence identity with each other and 68.80–84.40 % sequence identity with the other begomoviruses occurring in the Indian subcontinent. The closest identity (84.40 %) of the virus isolates was with Tomato leaf curl Sri Lanka virus (ToLCLKV). The results support that a new begomovirus species is affecting chilli in Sri Lanka and the name Chilli leaf curl Sri Lanka virus (ChiLCSLV) is proposed. Recombination analysis indicated that ChiLCSLV was a recombinant virus potentially originated from the begomoviruses prevailing in southern India and Sri Lanka. The genome of betasatellite associated with the two isolates consisted of 1366 and 1371 nucleotides and shared 95.2 % sequence identity with each other and 41.50–73.70 % sequence identity with the other betasatellite species. The results suggest that a new begomovirus betasatellite, Chilli leaf curl Sri Lanka betasatellite is associated with LCDC in Sri Lanka. This study demonstrates a new species of begomovirus and betasatellite complex is occurring in chilli in Sri Lanka and further shows that diverse begomovirus species are affecting chilli production in the Indian subcontinent.     

Identification of predictive MRI and functional biomarkers in a pediatric piglet traumatic brain injury model

Traumatic brain injury(TBI) at a young age can lead to the development of long-term functional impairments. Severity of injury is well demonstrated to have a strong influence on the extent of functional impairments; however, identification of specific magnetic resonance imaging(MRI) biomarkers that are most reflective of injury severity and functional prognosis remain elusive. Therefore, the objective of this study was to utilize advanced statistical approaches to identify clinically relevant MRI biomarkers and predict functional outcomes using MRI metrics in a translational large animal piglet TBI model. TBI was induced via controlled cortical impact and multiparametric MRI was performed at 24 hours and 12 weeks post-TBI using T1-weighted, T2-weighted, T2-weighted fluid attenuated inversion recovery, diffusion-weighted imaging, and diffusion tensor imaging. Changes in spatiotemporal gait parameters were also assessed using an automated gait mat at 24 hours and 12 weeks post-TBI. Principal component analysis was performed to determine the MRI metrics and spatiotemporal gait parameters that explain the largest sources of variation within the datasets. We found that linear combinations of lesion size and midline shift acquired using T2-weighted imaging explained most of the variability of the data at both 24 hours and 12 weeks post-TBI. In addition, linear combinations of velocity, cadence, and stride length were found to explain most of the gait data variability at 24 hours and 12 weeks post-TBI. Linear regression analysis was performed to determine if MRI metrics are predictive of changes in gait. We found that both lesion size and midline shift are significantly correlated with decreases in stride and step length. These results from this study provide an important first step at identifying relevant MRI and functional biomarkers that are predictive of functional outcomes in a clinically relevant piglet TBI model. This study was approved by the University of Georgia Institutional Animal Care and Use Committee(AUP: A2015 11-001) on December 22, 2015.     

Integration of light scattering with machine learning for label free cell detection

Light scattering has been used for label-free cell detection. The angular light scattering patterns from the cells are unique to them based on the cell size, nucleus size, number of mitochondria, and cell surface roughness. The patterns collected from the cells can then be classified based on different image characteristics. We have also developed a machine learning (ML) method to classify these cell light scattering patterns. As a case study we have used this light scattering technique integrated with the machine learning to analyze staurosporine-treated SH-SY5Y neuroblastoma cells and compare them to non-treated control cells. Experimental results show that the ML technique can provide a classification accuracy (treated versus non-treated) of over 90%. The predicted percentage of the treated cells in a mixed solution is within 5% of the reference (ground-truth) value and the technique has the potential to be a viable method for real-time detection and diagnosis.     

A prospective study on survival in cancer patients with and without venous thromboembolism

Retrospective population-based studies showed that in cancer patients venous thromboembolism (VTE) is associated with reduced survival. Master Oncology is a multicenter study in patients with solid advanced cancer aimed at assessing (1) risk factors for VTE using a case–control design, and (2) survival in cases (patients with VTE) and controls (patients without VTE). Survival data were prospectively collected for at least 10 months. Overall, 237 cases and 339 controls were included in the analysis. The following factors were found to be associated with an increased risk of VTE: body mass index (BMI; OR 2.02; 95 % CI 1.31–3.12 for ≥26 vs. <23 kg/m²), ECOG score (OR 2.14; 95 % CI 1.47–3.11 for grade 1, and 3.32; 95 % CI 1.64–6.00 for grade 2–3, compared to grade 0) and recent diagnosis of cancer (OR 1.90; 95 % CI 1.33–2.71 for <12 vs. ≥12 months). After an average prospective observation of 8.3 months, 136 cases (57.4 %) and 127 controls (37.5 %) died with a median survival of 8.7 (95 % CI 7.5–10.9) and 14.3 months (95 % CI 12.2–18.7), respectively, (Wilcoxon = 27.72, p < 0.001; multivariate hazard ratio 1.55; 95 % CI 1.21–2.00). Median survival time was reduced for both patients with symptomatic (Wilcoxon = 35.22, p < 0.001) and asymptomatic VTE (Wilcoxon = 4.63, p = 0.031). Patients with advanced solid cancer, high BMI, high ECOG score, and recent diagnosis of cancer are associated with an increased risk for VTE. Patients with both symptomatic and asymptomatic VTE have a reduced survival compared to those without VTE.     

Glutathionyl hemoglobin is elevated in iron deficiency anemia

There are few good biomarkers of iron deficiency anemia (IDA). Since IDA patients have evidence for increased oxidative stress, we used mass spectrometry (MS) [i.e. matrix-assisted laser desorption/ionization (MALDI) and electrospray ionization] to identify novel biomarkers. Using MALDI-MS, the following oxidative modifications of hemoglobin with the following mass-to-charge ratios were identified: 1,087.5 (α32-40), 1,545.7 (α17-31), 1,290.0 (β31-40) and 2,076.1 (β41-59). On electrospray ionization MS, the IDA patients had significantly elevated glutathionyl hemoglobin (GSHb) compared with the controls (16.9 ± 9.6 vs. 7.7 ± 3.7%; p = 0.002). GSHb levels correlated inversely with serum ferritin (Spearman rho -0.485; p = 0.003) and positively with serum transferrin receptor (0.460; p = 0.002). GSHb also demonstrated inverse correlations with hemoglobin (-0.512; p = 0.001), mean cell volume (-0.419; p = 0.026), serum iron (-0.446; p = 0.008) and transferrin saturation (-0.460; p = 0.008). For the first time, we show that GSHb is elevated in patients with IDA and has potential as a biomarker of this form of anemia.     

<Emphasis Type="Italic">PTEN</Emphasis>-mediated AKT activation contributes to the reduced apoptosis among Indian oral squamous cell carcinoma patients

Purpose  

The tumor suppressor gene PTEN negatively regulates Akt, a downstream mediator phosphoinositol 3-kinase. Several studies have reported the role of PTEN gene in Akt downregulation and apoptosis induction in different cancers and cell lines. However, the role of loss of PTEN expression in Akt activation and spontaneous apoptosis in oral squamous cell carcinoma clinical specimens is not well established.