Regulatory Role of Vitamin D Receptor Gene Variants of BsmI, ApaI, TaqI, and FokI Polymorphisms on Macrophage Phagocytosis and Lymphoproliferative Response to Mycobacterium tuberculosis Antigen in Pulmonary Tuberculosis

The regulatory role of vitamin D receptor (VDR) gene variants of Bsm I, Apa I, Taq I, and Fok I polymorphisms on vitamin D(3)-modulated macrophage phagocytosis with live Mycobacterium tuberculosis and lymphoproliferative response to M. tuberculosis culture filtrate antigen (CFA) was studied in patients with pulmonary tuberculosis (n = 46) and in normal healthy subjects (NHS) (n = 64). Vitamin D(3) at a concentration of 1 x 10(-7) M enhanced the phagocytic potential of normal subjects who had a phagocytic index of less than 20%. This increase was seen in subjects with the genotypes BB (p = 0.017), AA (p = 0.016), tt (p = 0.034), and FF (p = 0.013) and the extended genotype BBAAtt (p = 0.034). Normal subjects with BBAAtt performed better phagocytosis than individuals with bbaaTT genotype (p = 0.034). Vitamin D(3) at 10(-9), 10(-8), and 10(-7) M concentrations suppressed the lymphoproliferative response to CFA antigen in normal subjects. This decreased lymphocyte response was observed in normal individuals with the genotypes BB (p = 0.0009), tt (p = 0.016), and FF (p = 0.008) and the extended genotype BBAAtt (p = 0.02). Addition of vitamin D(3) had no significant effect on macrophage phagocytosis and lymphoproliferative response to CFA in pulmonary TB patients. This may be due to the unresponsive nature of the cells to the action of vitamin D(3) or the downregulated VDR expression by virtue of the disease, which renders them inactive. The genotypes BB, tt, and the extended genotype BBAAtt may be associated with increased expression of VDR which in turn regulate the action of vitamin D(3) and modulate the immune functions to M. tuberculosis in NHS.     

Open Classic Latarjet Procedure Performed Using Freehand Technique—Surgical Technique and Outcome

IntroductionLatarjet procedure is commonly performed for recurrent anterior shoulder instability with glenoid side bone loss. Classic Latarjet procedure can be performed using specially designed drill guides, jigs, or by freehand technique. Here we have described a technical note on classic Latarjet procedure performed with freehand technique utilizing simple rulers and caliper. The functional and radiological outcomes of our patients have also been analysed.Material and Methods149 open classic Latarjet procedures were performed using our technique between March 2015 and July 2018. The mean age of the patients was 32.95 years (Range 22–59 years). The functional outcome of the patients was measured using Western Ontario Shoulder Instability (WOSI) and Oxford Shoulder Instability Score (OSIS) at 2 years of follow-up. Screw and graft positioning were studied in 24 consecutive patients with a postoperative computed tomography (CT) scan.ResultsThere was no incidence of recurrent subluxation or dislocation post-surgery. Mean OSIS score increased from 15.63 ± 3.20 preoperatively to 42.44 ± 3.88 postoperatively (p value < 0.05). WOSI score decreased significantly from 62.54% ± 8.24 to 10.26 ± 6.33 postoperatively at 2-year follow-up (p value < 0.05). Postoperative CT scan also showed satisfactory screw placement in all patients.ConclusionOpen Latarjet procedure performed using freehand technique provides good functional and radiological outcomes in patients with recurrent anterior shoulder instability with glenoid side bone loss.Supplementary InformationThe online version contains supplementary material available at 10.1007/s43465-021-00385-7.     

Reproductive tract immune cells from pregnant women or those using depot medroxyprogesterone acetate show no excess susceptibility to HIV-1: Results of an ex vivo fusion assay

IntroductionEx vivo fusion assays offer an efficient method for studying HIV-1 entry associated with contraceptive use and pregnancy outside of cohort studies of HIV-1 incidence.MethodsWe measured ex vivo HIV-1 fusion to cervical or endometrial immune cells from three groups of women: pregnant, non-pregnant not using hormonal or intrauterine contraception, and using depot medroxyprogesterone acetate (DMPA).Results and conclusionsThere was no excess susceptibility to HIV-1 fusion of cells from pregnant women or DMPA users compared to controls. Although the number of target cells in endometrium was higher in DMPA users compared to controls, HIV-1 fusion was lower.ImplicationsIn ex vivo assays, HIV-1 showed no enhanced fusion to cervical immune cells from pregnant women or DMPA users compared to controls, and lower fusion to endometrial immune cells from DMPA users. This assay is useful for studying hormonal and contraceptive effects on HIV-1 entry into reproductive tract immune cells.     

Treat cancers by targeting survivin: Just a dream or future reality?

Since the discovery of survivin (BIRC5) as a cancer-related molecule by Grazia Ambrosini and Dario C. Altieri at 1997, our knowledge related to the function of this molecule has been extended from simple apoptosis inhibition to complicated, interlinked processes that involve interference of mitosis, apoptosis, autophagy, and even DNA repair recently. However, despite the growing amount of knowledge related to survivin in the last ten years, the development of survivin inhibitors or survivin-related molecular therapies is surprisingly and relatively slow as compared to other therapeutic inhibitors for cancer treatment. Here, the molecular functions of survivin and the progress of development of survivin-targeting therapies are discussed in detail. Functional differences between different survivin-specific inhibitors are discussed from both structural and biochemical point of views. This review also reveals different challenges that scientists are currently facing in the development of survivin inhibitors for clinical application. Finally, future directions for the development of survivin-targeted therapies are discussed in this review.     

Longitudinal MRI brain volume changes over one year in children with mucopolysaccharidosis types IIIA and IIIB

ObjectiveTo quantify changes in segmented brain volumes over 12 months in children with mucopolysaccharidosis types IIIA and IIIB (MPS IIIA and IIIB).MethodsIn order to establish suitable outcome measures for clinical trials, twenty-five children greater than 2 years of age were enrolled in a prospective natural history study of MPS IIIA and IIIB at Nationwide Children's Hospital. Data from sedated non-contrast brain 3 T MRIs and neuropsychological measures were reviewed from the baseline visit and at 12-month follow-up. No intervention beyond standard clinical care was provided. Age- and sex-matched controls were gathered from the National Institute of Mental Health Data Archive. Automated brain volume segmentation with longitudinal processing was performed using FreeSurfer.ResultsOf the 25 subjects enrolled with MPS III, 17 children (4 females, 13 males) completed at least one MRI with interpretable volumetric data. The ages ranged from 2.8 to 13.7 years old (average 7.2 years old) at enrollment, including 8 with MPS IIIA and 9 with MPS IIIB. At baseline, individuals with MPS III demonstrated reduced cerebral white matter and corpus callosum volumes, but greater volumes of the lateral ventricles, cerebellar cortex, and cerebellar white matter compared to controls. Among the 13 individuals with MPS III with two interpretable MRIs, there were annualized losses or plateaus in supratentorial brain tissue volumes (cerebral cortex ?42.10 ± 18.52 cm³/year [mean ± SD], cerebral white matter ?4.37 ± 11.82 cm³/year, subcortical gray matter ?6.54 ± 3.63 cm³/year, corpus callosum ?0.18 ± 0.62 cm³/yr) and in cerebellar cortex (?0.49 ± 12.57 cm³/year), with a compensatory increase in lateral ventricular volume (7.17 ± 6.79 cm³/year). Reductions in the cerebral cortex and subcortical gray matter were more striking in individuals younger than 8 years of age. Greater cerebral cortex volume was associated with higher fine and gross motor functioning on the Mullen Scales of Early Learning, while greater subcortical gray matter volume was associated with higher nonverbal functioning on the Leiter International Performance Scale. Larger cerebellar cortex was associated with higher receptive language performance on the Mullen, but greater cerebellar white matter correlated with worse adaptive functioning on the Vineland Adaptive Behavioral Scales and visual problem-solving on the Mullen.ConclusionsLoss or plateauing of supratentorial brain tissue volumes may serve as longitudinal biomarkers of MPS III age-related disease progression compared to age-related growth in typically developing controls. Abnormally increased cerebellar white matter in MPS III, and its association with worse performance on neuropsychological measures, suggest the possibility of pathophysiological mechanisms distinct from neurodegeneration-associated atrophy that warrant further investigation.     

4D radiobiological modelling of the interplay effect in conventionally and hypofractionated lung tumour IMRT

Objective:

To study the impact of the interplay between respiration-induced tumour motion and multileaf collimator leaf movements in intensity-modulated radiotherapy (IMRT) as a function of number of fractions, dose rate on population mean tumour control probability () using an in-house developed dose model.

Methods:

Delivered dose was accumulated in a voxel-by-voxel basis inclusive of tumour motion over the course of treatment. The effect of interplay on dose and was studied for conventionally and hypofractionated treatments using digital imaging and communications in medicine data sets. Moreover, the effect of dose rate on interplay was also studied for single-fraction treatments. Simulations were repeated several times to obtain for each plan.

Results:

The average variation observed in mean dose to the target volumes were −0.76% ± 0.36% for the 20-fraction treatment and −0.26% ± 0.68% and −1.05% ± 0.98% for the three- and single-fraction treatments, respectively. For the 20-fraction treatment, the drop in was −1.05% ± 0.39%, whereas for the three- and single-fraction treatments, it was −2.80% ± 1.68% and −4.00% ± 2.84%, respectively. By reducing the dose rate from 600 to 300 MU min⁻¹ for the single-fraction treatments, the drop in was reduced by approximately 1.5%.

Conclusion:

The effect of interplay on is negligible for conventionally fractionated treatments, whereas considerable drop in is observed for the three- and single-fraction treatments. Reduced dose rate could be used in hypofractionated treatments to reduce the interplay effect.

Advances in knowledge:

A novel in silico dose model is presented to determine the impact of interplay effect in IMRT treatments on .Respiration-induced organ motion represents a serious challenge regarding the accuracy of dose delivery in radiotherapy (RT) and its impact on clinical outcome. Lung tumours are the most common tumours affected by respiration-induced motion, and local failure (approximately 70% of the cases) is considered as a major cause of tumour-related deaths. Studies have highlighted the importance of dose escalation for improving local control in non-small-cell lung cancers (NSCLC).^1,2Since intensity-modulated RT (IMRT) has the potential to deliver higher doses with fewer normal tissue complications,³ IMRT is often used nowadays to treat lung tumours. Moreover, hypofractionated treatments have been shown to result in better clinical outcomes for medically inoperable early-stage lung tumours.^4–7 Better targeting accuracy coupled with superior normal tissue sparing and higher dose conformality, especially with smaller treatment fields used in stereotactic treatments, allows clinicians to prescribe extremely high doses in very few fractions (approximately three). With the advent of image-guided RT, this type of treatment is becoming increasingly common for lung RT. In conventional treatments where the fluence is uniform at the central portion of the fields, respiration-induced tumour motion causes dose blurring at the edges of the target volume, which can be accounted for by a sufficient planning target volume (PTV) margin. However, in multileaf collimator (MLC)-based IMRT delivery where the fluence is non-uniform across the fields, the interplay between respiration-induced tumour motion and the movement of MLC leaves can result in undesired motion artefacts in dose delivery.^8,9 Consequently, motion management or correction techniques such as tumour tracking or gating have been suggested for treating moving tumours with IMRT.^10–13 It should also be noted that lung tumours have one of the steepest dose–response curves (γ₅₀ = 3.9),¹⁴ which means that a small change in dose results in a relatively large change in tumour control probability (TCP). Although motion management techniques are currently available, it may not be possible to use such techniques for each patient either owing to time or resource constraints. Thus, it is important to understand and quantify the effect of tumour motion in IMRT treatments, that is, the interplay effect, in the absence of tumour tracking or gating. By quantifying, we mean not only in terms of absorbed dose, a purely physical quantity, but more importantly in terms of changes in the probability of local tumour control.Several studies have investigated the effect of respiration-induced tumour motion on IMRT treatments.^9,15–20 Jiang et al¹⁵ have investigated the effect of interplay for three different modes of IMRT delivery (step-and-shoot with 10 and 20 intensity levels, sliding window) using a 0.6-cm³ farmer chamber positioned at the centre of the artificial tumour in a moving phantom. They found that the mean dose to the moving tumour for all the fields varies from <2% to 3%, but it could be as high as 30% for a single field. They have also shown that the variation in dose is insensitive to the mode of delivery and the dose differences due to interplay decrease as the number of treatment fractions becomes large (approximately 30). This has been previously emphasized by Bortfeld et al⁹ who showed by statistical analysis that the mean dose to a moving tumour is insensitive to the delivery technique, and the standard deviation (SD) in dose for a 30-fraction treatment is generally <1% of the mean dose. However, the conclusion derived from point-dose measurements by Jiang et al does not provide a complete picture of the interplay effect to the overall tumour volume. Using two-dimensional (2D) film measurements, Berbeco et al²¹ have shown that the SD of the dose to a pixel inside the target volume can be as high as 2–4% for single-fraction treatments, which corresponds to stereotactic radiosurgery, although the effect is reduced to 0.4–0.7% with 30 fractions. According to their measurements, the maximum dose in the target varies <1%, while the minimum dose varies up to approximately 6%. This indicates that there could be considerable underdosage of the target volume even for treatments with large number of fractions and the effect of interplay is significant for hypofractionated treatments. In a recent study by Zhao et al²² in a three-fraction treatment, the results showed that the clinical target volume (CTV) could be considerably underdosed owing to the interplay effect in a Cyberknife® treatment (Accuray Inc., Sunnyvale, CA). Furthermore, Seco et al²³ have emphasized that reduced dose errors owing to the interplay effect in many-fraction treatments will not apply to hypofractionated treatments. Nevertheless, the effect of tumour motion and MLC leaves remains a concern for hypofractionated treatments, and this has been emphasized by American Association of Physicists in Medicine report 91.²⁴Although there are numerous studies addressing the issues of interplay effects in terms of dose variation in the tumour, studies quantifying the clinical significance of these dose variations are much rarer. Use of TCP as a metric would provide a more valuable insight into the true significance of the interplay effect. As mentioned by Niemierko,²⁵ it would be interesting to know the clinical significance of “x” amount of dose error and “y” amount of geometric error rather than mere variation in the dose. Duan et al¹⁸ have performed a TCP analysis using a moving phantom and found the TCP changes to be 2.3% and 4.3% for five- and single-fraction treatments. However, the volume of the target used in their study is fixed (4.5-cm diameter sphere). TCP values could significantly differ with the volume of the target even for the same prescribed dose with a uniform clonogen density in the CTV, which is the case in this study. Moreover, the TCP values provided were not calculated from a large number of simulations, which raises concern over its applicability for a population of patients.