Summary
Background
Fibrosis in ulcerative colitis has remained largely unexplored despite its clinical implications.
Aims
This cross‐sectional study was aimed at characterising the presence, ...anatomical location and degree of ulcerative colitis‐associated fibrosis and its possible link to clinical parameters.
Methods
Seven hundred and six individual tissue cross‐sections derived every 10 cm along the length of 89 consecutive Ulcerative colitis colectomy specimens were examined and compared to Crohn's disease colitis, diverticular disease and uninvolved areas from colorectal cancer patients. Degree of inflammation, fibrosis and morphometric measurements of all layers of the intestinal wall were evaluated. Three gastrointestinal pathologists independently assessed colon sections stained with haematoxylin and eosin, Masson trichrome and Sirius red. Clinical data were collected prospectively.
Results
Submucosal fibrosis was detected in 100% of ulcerative colitis colectomy specimens, but only in areas affected by inflammation. Submucosal fibrosis was associated with the severity of intestinal inflammation (Spearman correlations rho (95% confidence interval): 0.58 (P < 0.001) and histopathological changes of chronic mucosal injury, but not active inflammation. Colectomy for refractory disease rather than presence of dysplasia was associated with increased fibrosis and a thicker muscularis mucosae, whereas a thinner muscularis mucosae was associated with anti‐tumour necrosis factor therapy. No feature on endoscopic mucosal biopsies could predict the underlying amount of fibrosis or the thickness of the muscularis mucosae.
Conclusions
A significant degree of fibrosis and muscularis mucosae thickening should be considered as common complications of chronic progressive ulcerative colitis. These features may have clinical consequences such as motility abnormalities and increased wall stiffness.
CRISPR-Cas adaptive immune systems in prokaryotes boast a diversity of protein families and mechanisms of action, where most systems rely on protospacer-adjacent motifs (PAMs) for DNA target ...recognition. Here, we developed an in vivo, positive, and tunable screen termed PAM-SCANR (PAM screen achieved by NOT-gate repression) to elucidate functional PAMs as well as an interactive visualization scheme termed the PAM wheel to convey individual PAM sequences and their activities. PAM-SCANR and the PAM wheel identified known functional PAMs while revealing complex sequence-activity landscapes for the Bacillus halodurans I-C (Cascade), Escherichia coli I-E (Cascade), Streptococcus thermophilus II-A CRISPR1 (Cas9), and Francisella novicida V-A (Cpf1) systems. The PAM wheel was also readily applicable to existing high-throughput screens and garnered insights into SpyCas9 and SauCas9 PAM diversity. These tools offer powerful means of elucidating and visualizing functional PAMs toward accelerating our ability to understand and exploit the multitude of CRISPR-Cas systems in nature.
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•PAM-SCANR is an in vivo, positive screen to comprehensively reveal functional PAMs•The PAM wheel offers a means to visualize PAM sequences and relative activities•Functional PAMs elucidated for canonical types I-C, I-E, II-A (Cas9), and V-A (Cpf1)•Functional PAMs encompass uneven sequence-activity landscapes
Leenay et al. developed a high-throughput screen and visualization scheme to rapidly identify and represent functional PAMs for CRISPR-Cas systems. Using their approach on four canonical CRISPR systems, they unearthed diverse PAM sequences and variable activities, with implications for CRISPR biology and related technologies.
The first evidence of spin alignment of vector mesons ( K*0 and ϕ ) in heavy-ion collisions at the Large Hadron Collider (LHC) is reported. The spin density matrix element ρ 00 is measured at ...midrapidity ( | y | < 0.5 ) in Pb-Pb collisions at a center-of-mass energy ( √sNN ) of 2.76 TeV with the ALICE detector. ρ 00 values are found to be less than 1/3 (1/3 implies no spin alignment) at low transverse momentum ( p T < 2 GeV / c ) for K*0 and ϕ at a level of 3 σ and 2 σ , respectively. No significant spin alignment is observed for the K0S meson ( spin = 0 ) in Pb-Pb collisions and for the vector mesons in p p collisions. The measured spin alignment is unexpectedly large but qualitatively consistent with the expectation from models which attribute it to a polarization of quarks in the presence of angular momentum in heavy-ion collisions and a subsequent hadronization by the process of recombination.
To determine genomic alterations in head and neck squamous cell carcinoma (HNSCC) using formalin-fixed, paraffin-embedded (FFPE) tumors obtained through routine clinical practice, selected ...cancer-related genes were evaluated and compared with alterations seen in frozen tumors obtained through research studies.
DNA samples obtained from 252 FFPE HNSCC were analyzed using next-generation sequencing-based (NGS) clinical assay to determine sequence and copy number variations in 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. Human papillomavirus (HPV) status was determined by presence of the HPV DNA sequence in all samples and corroborated with high-risk HPV in situ hybridization (ISH) and p16 immunohistochemical (IHC) staining in a subset of tumors. Sequencing data from 399 frozen tumors in The Cancer Genome Atlas and University of Chicago public datasets were analyzed for comparison.
Among 252 FFPE HNSCC, 84 (33%) were HPV positive and 168 (67%) were HPV negative by sequencing. A subset of 40 tumors with HPV ISH and p16 IHC results showed complete concordance with NGS-derived HPV status. The most common genes with genomic alterations were PIK3CA and PTEN in HPV-positive tumors and TP53 and CDKN2A/B in HPV-negative tumors. In the pathway analysis, the PI3K pathway in HPV-positive tumors and DNA repair-p53 and cell cycle pathways in HPV-negative tumors were frequently altered. The HPV-positive oropharynx and HPV-positive nasal cavity/paranasal sinus carcinoma shared similar mutational profiles.
The genomic profile of FFPE HNSCC tumors obtained through routine clinical practice is comparable with frozen tumors studied in research setting, demonstrating the feasibility of comprehensive genomic profiling in a clinical setting. However, the clinical significance of these genomic alterations requires further investigation through application of these genomic profiles as integral biomarkers in clinical trials.
At sufficiently high temperature and energy density, nuclear matter undergoes a transition to a phase in which quarks and gluons are not confined: the quark-gluon plasma (QGP). Such an exotic state ...of strongly interacting quantum chromodynamics matter is produced in the laboratory in heavy nuclei high-energy collisions, where an enhanced production of strange hadrons is observed. Strangeness enhancement, originally proposed as a signature of QGP formation in nuclear collisions, is more pronounced for multi-strange baryons. Several effects typical of heavy-ion phenomenology have been observed in high-multiplicity proton-proton (pp) collisions, but the enhanced production of multi-strange particles has not been reported so far. Here we present the first observation of strangeness enhancement in high-multiplicity proton-proton collisions. We find that the integrated yields of strange and multi-strange particles, relative to pions, increases significantly with the event charged-particle multiplicity. The measurements are in remarkable agreement with the p-Pb collision results, indicating that the phenomenon is related to the final system created in the collision. In high-multiplicity events strangeness production reaches values similar to those observed in Pb-Pb collisions, where a QGP is formed.
Genetic variations of Toll like receptor 4 (TLR4) and CXC-chemokine receptor type1 (CXCR1), the key elements of innate immune system and their association with urinary tract infection (UTI) were ...studied in general population. In present study we investigate genetic variation of these genes in diabetic patients (3 to 4 times higher prevalence of UTI in comparison to general population).
A total 1100 subjects (318 diabetic patients with UTI, 324 diabetic patients without UTI, 200 non-diabetic UTI patients and 260 age matched healthy control) were enrolled in the study. SNPs of TLR4 rs4986790, rs4986791 and CXCR1 rs2234671 was assessed by PCR-RFLP and PCR-SSP respectively.
Statistical analysis revealed that A/G genotype and G allele of TLR4 rs4986790 are significantly associated with UTI in both diabetics and nondiabetic patients in comparison to healthy control. Similarly CT genotype and T allele of TLR4 rs4986791 are also significantly associated with UTI in both groups. We also found that prevalence of A/G genotype of TLR4 rs4986790 and CT genotype of TLR4 rs4986791 are significantly higher in patients of diabetes with UTI in comparison to diabetic patients without UTI. We did not find any association of CXCR1 rs2234671 polymorphism with UTI by comparing with any group.
We found that TLR4 rs4986790 and rs4986791 gene polymorphism is a risk for UTI development in both diabetic and nondiabetic patients in north Indian population.
•AG genotype and G allele of TLR4 rs4986790 was significantly associated with UTI diabetics and nondiabetic patients.•Similarly CT genotype and T allele of TLR4 rs4986791 was also significantly associated with UTI in diabetics and nondiabetic patients.•CXCR1 rs2234671 polymorphism was not associated with UTI.•The TLR4 gene polymorphism increases susceptibility for UTI.
A
bstract
We report the measured transverse momentum (
p
T
) spectra of primary charged particles from pp, p-Pb and Pb-Pb collisions at a center-of-mass energy
s
N
N
=
5.02
TeV in the kinematic range ...of 0
.
15
< p
T
<
50 GeV/
c
and |
η
|
<
0
.
8. A significant improvement of systematic uncertainties motivated the reanalysis of data in pp and Pb-Pb collisions at
s
N
N
=
2.76
TeV, as well as in p-Pb collisions at
s
N
N
=
5.02
TeV, which is also presented. Spectra from Pb-Pb collisions are presented in nine centrality intervals and are compared to a reference spectrum from pp collisions scaled by the number of binary nucleon-nucleon collisions. For central collisions, the
p
T
spectra are suppressed by more than a factor of 7 around 6–7 GeV/
c
with a significant reduction in suppression towards higher momenta up to 30 GeV/
c
. The nuclear modification factor
R
pPb
, constructed from the pp and p-Pb spectra measured at the same collision energy, is consistent with unity above 8 GeV/
c
. While the spectra in both pp and Pb-Pb collisions are substantially harder at
s
N
N
=
5.02
TeV compared to 2.76 TeV, the nuclear modification factors show no significant collision energy dependence. The obtained results should provide further constraints on the parton energy loss calculations to determine the transport properties of the hot and dense QCD matter.
In this paper, a new technique for designing of a stable digital infinite impulse response filter, with improved performance in passband and stopband regions using quantum particle swarm optimization ...(QPSO) and artificial bee colony (ABC) algorithm, is explored in frequency domain. In the proposed method, QPSO technique is modified with exploiting the novelty of search and replacement mechanism of scout bee from ABC algorithm. For this purpose, a new design problem is constructed as a nonlinear minimization of mean square error between the designed and desired filter responses in passband, stopband, and transition band simultaneously, allowing permissible ripples in passband and stopband. Efficiency of the proposed technique is measured by several attributes like passband error, stopband error, total squared error (SE), maximum stopband attenuation, maximum passband error
e
pb
max
, passband ripple, and maximum phase deviation in passband. Experimental results evidence that a significant reduction is achieved in sum of the SE in passband and stopband from 12 to 54%, and the performance is not degraded due to quantization and truncation process. However, computation time in term of CPU time is increased from 0.77 to 4.1%, along with 2.62–7.43% hike in number of function evaluation, when compared to QPSO. A comparative study reveals that the proposed method yields better fidelity parameter as compared other evolutionary algorithms such as gravitational search algorithm, genetic algorithm, and variants of PSO. The proposed technique is also suitable for higher filter taps.
Patients with HPV+ oropharyngeal squamous cell carcinoma were assigned to dose and volume de-escalated radiotherapy (RT) or chemoradiotherapy (CRT) based on response to induction chemotherapy in an ...effort to limit treatment-related toxicity while preserving efficacy.
Patients were classified as low-risk (≤T3, ≤N2B, ≤10 pack-year history) or high-risk (T4 or ≥N2C or >10 PYH). After three cycles of carboplatin/nab-paclitaxel, response was assessed using Response Evaluation Criteria in Solid Tumors 1.1. Low-risk patients with ≥50% response received 50 Gray (Gy) RT (RT50) while low-risk patients with 30%–50% response or high-risk patients with ≥50% response received 45 Gy CRT (CRT45). Patients with lesser response received standard-of-care 75 Gy CRT (CRT75). RT/CRT was limited to the first echelon of uninvolved nodes. The primary end point was 2-year progression-free survival compared with a historic control of 85%. Secondary end points included overall survival and toxicity.
Sixty-two patients (28 low risk/34 high risk) were enrolled. Of low-risk patients, 71% received RT50 while 21% received CRT45. Of high-risk patients, 71% received CRT45. With a median follow-up of 29 months, 2-year PFS and OS were 95% and 100% for low-risk patients and 94% and 97% for high-risk patients, respectively. The overall 2-year PFS was 94.5% and within the 11% noninferiority margin for the historic control. Grade 3+ mucositis occurred in 30%, 63%, and 91% of the RT50, CRT45, and CRT75 groups, respectively (P = 0.004). Rates of any PEG-tube use were 0%, 31%, and 82% for RT50, CRT45, and CRT75 groups, respectively (P < 0.0001).
Induction chemotherapy with response and risk-stratified dose and volume de-escalated RT/CRT for HPV+ OPSCC is associated with favorable oncologic outcomes and reduced acute and chronic toxicity. Further evaluation of induction-based de-escalation in large multicenter studies is justified.
Clinical trials.gov identifier: NCT02258659.
In this paper, a hybrid optimization technique based on particle swarm optimization (PSO) and artificial bee colony (ABC) algorithm is presented for the optimal design of infinite impulse response ...(IIR) filter with low quantization effect. In this method, different variants of PSO have been exhaustively tested, and the time varying coefficients-PSO (TVC-PSO) is used to formulate a new hybrid technique for better exploitation and exploration, which is further modified by sorting and replacement mechanism of Scout Bee from ABC algorithm. For designing IIR filter, an objective function is constructed that satisfies the absolute error including peak ripples in passband and stopband regions in frequency domain, while stability of designed filter is confirmed by exploiting the lattice form structure during iterative computation that also reduces computation complexity. Several attributes such as passband error
(
e
p
)
, stopband error
(
e
s
)
, and stopband attenuation
(
A
s
)
are used to measure the performance of proposed algorithm. The simulation results presented in this paper evidence that this technique can be effectively used for designing digital IIR filter with higher filter taps, and low quantization effect for fixed number of bits.
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