168 research outputs found
Regulatory T cell frequency in patients with melanoma with different disease stage and course, and modulating effects of high-dose interferon-α 2b treatment
<p>Abstract</p> <p>Background</p> <p>High-dose interferon-alpha 2b (IFN-α 2b) is the only approved systemic therapy in the United States for the adjuvant treatment of melanoma. The study objective was to explore the immunomodulatory mechanism of action for IFN-α 2b by measuring serum regulatory T cell (Treg), serum transforming growth factor-β (TGF-β), interleukin (IL)-10, and autoantibody levels in patients with melanoma treated with the induction phase of the high-dose IFN-α 2b regimen.</p> <p>Methods</p> <p>Patients with melanoma received IFN-α 2b administered intravenously (20 MU/m<sup>2 </sup>each day from day 1 to day 5 for 4 consecutive weeks). Serum Treg levels were measured as whole lymphocytes in CD4<sup>+ </sup>cells using flow cytometry while TGF-β, IL-10, and autoantibody levels were measured using enzyme-linked immunosorbent assays.</p> <p>Results</p> <p>Twenty-two patients with melanoma received IFN-α 2b treatment and were evaluated for Treg levels. Before treatment, Treg levels were significantly higher in patients with melanoma when compared with data from 20 healthy subjects (<it>P </it>= 0.001; Mann-Whitney test). Although a trend for reduction of Treg levels following IFN-α 2b treatment was observed (average decrease 0.29% per week), statistical significance was not achieved. Subgroup analyses indicated higher baseline Treg levels for stage III versus IV disease (<it>P </it>= 0.082), early recurrence versus no recurrence (<it>P </it>= 0.017), deceased versus surviving patients (<it>P = </it>0.021), and preoperative neoadjuvant versus postoperative adjuvant treatment groups (not significant). No significant effects were observed on the levels of TGF-β, IL-10, and autoantibodies in patients with melanoma treated with IFN-α 2b.</p> <p>Conclusions</p> <p>Patients with melanoma in this study showed increased basal levels of Treg that may be relevant to their disease and its progression. Treg levels shifted in patients with melanoma treated with IFN-α 2b, although no firm conclusions regarding the role of Tregs as a marker of treatment response or outcome can be made at present.</p
Effect of bio-engineering on size, shape, composition and rigidity of bacterial microcompartments
Bacterial microcompartments (BMCs) are proteinaceous organelles that are found in a broad range of bacteria and are composed of an outer shell that encases an enzyme cargo representing a specific metabolic process. The outer shell is made from a number of different proteins that form hexameric and pentameric tiles, which interact to allow the formation of a polyhedral edifice. We have previously shown that the Citrobacter freundii BMC associated with 1,2-propanediol utilization can be transferred into Escherichia coli to generate a recombinant BMC and that empty BMCs can be formed from just the shell proteins alone. Herein, a detailed structural and proteomic characterization of the wild type BMC is compared to the recombinant BMC and a number of empty BMC variants by 2D-gel electrophoresis, mass spectrometry, transmission electron microscopy (TEM) and atomic force microscopy (AFM). Specifically, it is shown that the wild type BMC and the recombinant BMC are similar in terms of composition, size, shape and mechanical properties, whereas the empty BMC variants are shown to be smaller, hollow and less malleable
NGTS-13b: A hot 4.8 Jupiter-mass planet transiting a subgiant star
We report the discovery of the massive hot Jupiter NGTS-13b by the Next
Generation Transit Survey (NGTS). The V = 12.7 host star is likely in the
subgiant evolutionary phase with log g = 4.04 0.05, T =
5819 73 K, M = 1.30 M, and R =
1.79 0.06 R. NGTS detected a transiting planet with a period of
P = 4.12 days around the star, which was later validated with the Transiting
Exoplanet Survey Satellite (TESS; TIC 454069765). We confirm the planet using
radial velocities from the CORALIE spectrograph. Using NGTS and TESS full-frame
image photometry combined with CORALIE radial velocities we determine NGTS-13b
to have a radius of R = 1.142 0.046 R, mass of M =
4.84 0.44 M and eccentricity e = 0.086 0.034. Some previous
studies suggest that 4 M may be a border between two separate
formation scenarios (e.g., core accretion and disk instability) and that
massive giant planets share similar formation mechanisms as lower-mass brown
dwarfs. NGTS-13b is just above 4 M making it an important addition to
the statistical sample needed to understand the differences between various
classes of substellar companions. The high metallicity, [Fe/H] = 0.25
0.17, of NGTS-13 does not support previous suggestions that massive giants are
found preferentially around lower metallicity host stars, but NGTS-13b does
support findings that more massive and evolved hosts may have a higher
occurrence of close-in massive planets than lower-mass unevolved stars
NGTS discovery of a highly inflated Saturn-mass planet and a highly irradiated hot Jupiter: NGTS-26 b and NGTS-27 b
We report the discovery of two new transiting giant exoplanets NGTS-26 b and NGTS-27 b by the Next Generation Transit Survey (NGTS). NGTS-26 b orbits around a G6-type main sequence star every 4.52 days. It has a mass of 0.29-0.06+0.07 MJup and a radius of 1.33-0.05+0.06 RJup making it a Saturn-mass planet with a highly inflated radius. NGTS-27 b orbits around a slightly evolved G3-type star every 3.37 days. It has a mass of 0.59-0.07+0.10 MJup and a radius of 1.40±0.04 RJup, making it a relatively standard hot Jupiter. The transits of these two planetary systems were re-observed and confirmed in photometry by the SAAO 1.0-m telescope, 1.2-m Euler Swiss telescope as well as the TESS spacecraft, and their masses were derived spectroscopically by the CORALIE, FEROS and HARPS spectrographs. Both giant exoplanets are highly irradiated by their host stars and present an anomalously inflated radius, especially NGTS-26 b which is one of the largest objects among peers of similar mass
Targeting survivin and p53 in pediatric acute lymphoblastic leukemia
Despite advances in treatment and outcomes for patients with pediatric acute lymphoblastic leukemia (ALL), there continue to be subsets of patients who are refractory to standard chemotherapy and hematopoietic stem cell transplant. Therefore, novel gene targets for therapy are needed to further advance treatment for this disease. RNA interference technology has identified survivin as a potential therapeutic target. Survivin, a member of the inhibitor of apoptosis (IAP) proteins and chromosome passenger complex, is expressed in hematologic malignancies and overexpressed in relapsed pediatric ALL. Our studies show that survivin is uniformly expressed at high levels in multiple pediatric ALL cell lines. Furthermore, silencing of survivin expression in pediatric ALL cell lines as well as primary leukemic blasts reduces viability of these cells. This includes cell lines derived from patients with relapsed disease featuring cytogenetic anomalies such as t(12;21), Philadelphia chromosome t(9;22), t(1;19) as well as a cell line carrying t(17;19) from a patient with de novo ALL. Furthermore, inhibition of survivin increases p53-dependent apoptosis that can be rescued by inhibition of p53. Finally, a screen of randomly selected primary patient samples confirms that survivin-specific small interfering RNA and survivin-targeted drug, YM155, effectively reduce viability of leukemic blasts
NGTS-11 b (TOI-1847 b): A Transiting Warm Saturn Recovered from a TESS Single-transit Event
We report the discovery of NGTS-11 b (=TOI-1847 b), a transiting Saturn in a
35.46-day orbit around a mid K-type star (Teff=5050 K). We initially identified
the system from a single-transit event in a TESS full-frame image light-curve.
Following seventy-nine nights of photometric monitoring with an NGTS telescope,
we observed a second full transit of NGTS-11 b approximately one year after the
TESS single-transit event. The NGTS transit confirmed the parameters of the
transit signal and restricted the orbital period to a set of 13 discrete
periods. We combined our transit detections with precise radial velocity
measurements to determine the true orbital period and measure the mass of the
planet. We find NGTS-11 b has a radius of 0.817+0.028-0.032 , a mass of
0.344+0.092-0.073 , and an equilibrium temperature of just 435+34-32 K,
making it one of the coolest known transiting gas giants. NGTS-11 b is the
first exoplanet to be discovered after being initially identified as a TESS
single-transit event, and its discovery highlights the power of intense
photometric monitoring in recovering longer-period transiting exoplanets from
single-transit events
Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy
Background
A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets.
Methods
Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis.
Results
A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001).
Conclusion
We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty
Expression of different survivin variants in gastric carcinomas: first clues to a role of survivin-2B in tumour progression
Survivin is a novel member of the inhibitor of apoptosis family and determines the susceptibility of tumour cells to pro-apoptotic stimuli. Recently, we identified two novel alternative splice variants of survivin, differing in their anti-apoptotic properties: whereas the anti-apoptotic potential of survivin-ΔEx3 is preserved, survivin-2B has lost its anti-apoptotic potential and may act as a naturally occurring antagonist of survivin. Because the in vivo expression of these alternative splice variants has not been explored so far, we analysed gastric carcinomas of different histological subtypes, grades and stages. Since no antibodies are currently available to determine the novel splice variants, quantitative reverse transcriptase polymerase chain reaction was performed, using RNA samples obtained from 30 different gastric carcinomas. Polymerase chain reactions products were quantified by densitometric evaluation. We found that all gastric carcinomas, irrespective of their histological types, grades or stages, express survivin-ΔEx3, survivin-2B and survivin, the latter being the dominant transcript. Comparing the disease stages I+II with III+IV, expression of survivin and survivin-ΔEx3 remained unchanged. In contrast, a significant (P=0.033) stage-dependent decrease in the expression of survivin-2B became evident. Our study demonstrates for the first time the expression of alternative splice variants in gastric carcinomas and provides a first clue to a role of survivin-2B in tumour progression
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