Preliminary clinical outcomes of patients treated with vaginal brachytherapy alone using multi-channel vaginal brachytherapy applicator in operated early-stage endometrial cancer

BackgroundRecommendations for adjuvant treatment for postoperative, early-stage endometrial cancer varies from observation through vaginal brachytherapy alone to pelvic radiation. While observation alone can lead to recurrence, external radiotherapy has increased morbidity. The aim of this study is to show our results with vaginal brachytherapy alone using a multichannel applicator for treatment of early-stage endometrial cancer.Materials and methodsConsecutive patients undergoing vaginal brachytherapy alone following surgery for early-stage endometrial cancer were examined. A Miami multichannel vaginal brachytherapy applicator was used to deliver HDR brachytherapy in 62 patients from May 2013 to June 2018. CT scan-based images guided planning. A dose of 5.5–6.5 Gy × 4 fractions was prescribed 5 mm from the surface of the applicator.ResultsAt a median follow up of 19 months (6–48 months), 93% of patients treated were alive with no recurrence. Two patients had only local recurrence, and 1 was salvaged with external radiotherapy and chemotherapy. There was only one nodal failure and 2 distant failures. There was no grade 2 or higher vaginal, gastrointestinal or genitourinary toxicity.ConclusionVaginal brachytherapy alone using a multichannel applicator can be considered for early-stage endometrial cancers without compromising outcomes.     

Comparison of X-ray crystal structures of a tetradecamer sequence d(CCCGGGTACCCGGG)2 at 1.7 Å resolution

We present here a comparison of three different X-ray crystal structures of DNA tetradecamer sequence d(CCCGGGTACCCGGG)₂ all at about 1.7 Å resolution. The sequence was designed as an attempt to form a DNA four-way junction with A-type helical arms. However, in the presence of zinc, magnesium, and in the absence of any metal ion, it does not take up the junction structure, but forms an A-type double helix. This allowed us to study possible conformational changes in the double helix due to the presence of metal ions. Upon addition of the zinc ion, there is a change in the space group from P4₁2₁2 to P4₁. The overall conformation of the duplex remains the same. There are small changes in the interaction of the metal ions with the DNA. In the zinc-bound structure, there are two zinc ions that show direct interaction with the N7 atoms of terminal G₁₃ bases at either end of the molecule. There are small changes in the interhelical contacts. The consequence of these differences is to break some of the symmetry and change the space group.     

miR‐214 activates TP53 but suppresses the expression of RELA,CTNNB1, and STAT3 in human cervical and colorectal cancer cells

High Mobility Group AT‐hook 1 (HMGA1) was identified as a target of miR‐214 in human cervical and colorectal cancers (CaCx and CRC) in a previous study. While the expression of miR‐214 remains suppressed, HMGA1 behaves as a potent oncogene and plays crucial roles in several aberrant signalling pathways by interacting with intermediates like RELA, CTNNB1, STAT3, and TP53 in CaCx and CRC. Hypothetically, miR‐214 should be able to regulate the stabilization of some of these intermediates through the regulation of HMGA1. This was assessed by ectopically expressing miR‐214 or complementarily, by inhibiting the expression of HMGA1. In promoter luciferase assays, miR‐214 inhibited NF‐κB and Wnt activities but elevated TP53 activity in cancer cells. Further, miR‐214 suppressed the expression of HMGA1, RELA, CTNNB1, and STAT3 while elevating TP53 levels, similar to when small interfering RNA (siRNA) against HMGA1 was used, as revealed by Western blotting. It is suggested that poor expression of miR‐214, commonly reported in CaCx and CRC tissues, may not only result in the sustained expression of HMGA1 but also that of RELA, CTNNB1, and STAT3, and a congruent suppression of TP53 during cancer initiation/progression. These several states are, however, reversed when miR‐214 is reintroduced and could explain the tumour suppressive functions observed in earlier studies. Further studies are, however, required to reveal how microRNA‐mediated regulation of HMGA1 expression may affect individual signalling pathways in CaCx and CRC. Current results reveal that miR‐214 is not only able to regulate the expression of its direct target, HMGA1, but also that of a few signalling intermediates like TP53, RELA, CTNNB1, and STAT3, with which HMGA1 interacts. These intermediates play crucial roles in signalling pathways commonly deregulated in human CaCx and CRC. Hence, it is proposed that miR‐214 might act as a tumour suppressor by regulating several aberrant signalling pathways through HMGA1. This knowledge has the potential to help design novel therapeutic strategies in CaCx and CRC.     

High initial IgG antibody levels against Orientia tsutsugamushi are associated with an increased risk of severe scrub typhus infection

BackgroundScrub typhus is a dominant cause of febrile illness in many parts of Asia. Immunity is limited by the great strain diversity of Orientia tsutsugamushi. It is unclear whether previous infection protects from severe infection or enhances the risk.Methods/principal findingsWe studied IgG antibody levels against O. tsutsugamushi at presentation in 636 scrub typhus patients using enzyme-linked immunosorbent assays (ELISA). The association between ELISA optical density (OD) and risk of severe infection was modelled using Poisson regression. OD was categorised as low (<1.0), intermediate (1.0 to 2.9), and high (≥3.0). OD was also modelled as a continuous variable (cubic spline). Median age of cases was 41 years (range 0–85), with 37% having severe infection. Compared to the low category, the age-adjusted risk of severe infection was 1.5 times higher in the intermediate category (95%CI 1.2, 1.9), and 1.3 times higher in the high category (95%CI 1.0, 1.7). The effect was stronger in cases <40 years, doubling the risk in the intermediate and high categories compared to the low category. The effect was more pronounced in cases tested within 7 days of fever onset when IgG ODs are more likely to reflect pre-infection levels.Conclusions/SignificanceIntermediate and high IgG antibody levels at the time of diagnosis are associated with a higher risk of severe scrub typhus infection. The findings may be explained by severe infection eliciting an accelerated IgG response or by previous scrub typhus infection enhancing the severity of subsequent episodes.     

Multiply accelerated ReaxFF molecular dynamics: coupling parallel replica dynamics with collective variable hyper dynamics

ABSTRACT

To tackle the time scales required to study complex chemical reactions, methods performing accelerated molecular dynamics are necessary even with the recent advancement in high-performance computing. A number of different acceleration techniques are available. Here we explore potential synergies between two popular acceleration methods – Parallel Replica Dynamics (PRD) and Collective Variable Hyperdynamics (CVHD), by analysing the speedup obtained for the pyrolysis of n-dodecane. We observe that PRD?+?CVHD provides additional speedup to CVHD by reaching the required time scales for the reaction at an earlier wall-clock time. Although some speedup is obtained with the additional replicas, we found that the effectiveness of the inclusion of PRD is depreciated for systems where there is a dramatic increase in reaction rates induced by CVHD. Similar observations were made in the simulation of ethylene-carbonate/Li system, which is inherently more reactive than pyrolysis, indicate that the speedup obtained via the combination of the two acceleration methods can be generalised to most practical chemical systems.     

Molecular classification of zebrafish retinal ganglion cells links genes to cell types to behavior

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Trophoblast differentiation of human embryonic stem cells

Molecular mechanisms regulating human trophoblast differentiation remain poorly understood due to difficulties in obtaining primary tissues from very early developmental stages in humans. Therefore, the use of human embryonic stem cells (hESCs) as a source for generating trophoblast tissues is of significant interest. Trophoblast-like cells have been obtained through treatment of hESCs with bone morphogenetic protein (BMP) or inhibitors of activin/nodal/transforming growth factor-β signaling, or through protocols involving formation of embryoid bodies (EBs); however, there is controversy over whether hESC-derived cells are indeed analogous to true trophoblasts found in vivo. In this review, we provide an overview of previously described efforts to obtain trophoblasts from hESCs. We also discuss the merits and limitations of hESCs as a source of trophoblast derivatives.