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Oral squamous cell carcinomas (OSCC) remain a major healthcare burden in Asian countries. In Pakistan alone, it is the most common cancer in males and second only to breast cancer in females. Alarmingly, treatment options for OSCC...
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Oral squamous cell carcinomas (OSCC) remain a major healthcare burden in Asian countries. In Pakistan alone, it is the most common cancer in males and second only to breast cancer in females. Alarmingly, treatment options for OSCC remain limited. With this context, investigations made to explore the inflammatory milieu of OSCC become highly relevant, with the hope of practicing immunotherapeutic approaches to address this highly prevalent tumor. We investigated the newly identified innate lymphoid cells (ILCs) and associated cytokines in well-defined human oral squamous cell carcinoma (OSCC) as well as in a 7,12-dimethylbenz[a]anthracene (DMBA)-induced murine model of OSCC using flow cytometry and quantitative real-time polymerase chain reaction (qPCR). We further went on to explore molecular circuitry involved in OSCC by developing a murine model of OSCC and using an α-Thy1 antibody to inhibit ILCs. Amongst the ILCs that we found in human OSCC, ILC3 (23%) was the most abundant, followed by ILC2 (17%) and ILC1 (1%). Mice were divided into four groups: DMBA (n = 33), DMBA+antibody (Ab) (n = 30), acetone (n = 5), and control (n = 5). In murine OSCC tissues, ILC1 and ILC3 were down-infiltrated, while ILC2 remained unchanged compared to controls. Interestingly, compared to the controls (DMBA group), mice treated with the α-Thy1 antibody showed fewer numbers of large tumors, and a larger percentage of these mice were tumor-free at this study’s end point. We present novel data on the differential expansion/downsizing of ILCs in OSCC, which provides a pivotal basis to dive deeper into molecular circuitry and the OSCC tumor niche to devise novel diagnostic, therapeutic, and prognostic strategies to prevent/treat oral cancers.
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Aim: The goal of this study was to determine whether bacterial clearance in a rodent model would be impaired upon exposure to gold, silver or silica nanoparticles (NPs). Materials & methods: Mice received weekly injections of NPs followed by a challenge of Listeria monocytogenes (LM). On days 3 and 10 after LM injections, the animals were sacrificed and their tissues were collected for elemental analysis, electron microscopy and LM count determination. Results: The untreated and NP-treated animals cleared LM at the same rate suggesting that bioaccumulation of NPs did not increase the animals' susceptibility to bacterial infection. Conclusion: The data from this study indicate that the bioaccumulation of NPs does not significantly affect the ability to react to a bacterial challenge....
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Aim: The goal of this study was to determine whether bacterial clearance in a rodent model would be impaired upon exposure to gold, silver or silica nanoparticles (NPs). Materials & methods: Mice received weekly injections of NPs followed by a challenge of Listeria monocytogenes (LM). On days 3 and 10 after LM injections, the animals were sacrificed and their tissues were collected for elemental analysis, electron microscopy and LM count determination. Results: The untreated and NP-treated animals cleared LM at the same rate suggesting that bioaccumulation of NPs did not increase the animals' susceptibility to bacterial infection. Conclusion: The data from this study indicate that the bioaccumulation of NPs does not significantly affect the ability to react to a bacterial challenge.
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Vitamin D (Vit D) deficiency (VDD) associated with diverse health conditions, is commonly treated with Vit D3 supplements. However, the gastrointestinal (GI) absorption (efficacy) of Vit D3 different formulations has not been well...
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Vitamin D (Vit D) deficiency (VDD) associated with diverse health conditions, is commonly treated with Vit D3 supplements. However, the gastrointestinal (GI) absorption (efficacy) of Vit D3 different formulations has not been well studied.We aimed to compare the efficacy of an innovative phospholipids-sucrester matrix biodelivery vehiclebased (sucrosomial) orodispersible Vit D3 preparation against a reference chewable tablet and soft gel capsule (SGC) Vit D3 formulations in Vit D deficient healthy adults.In study 1, 25 subjects were randomised to receive a weekly single dose of 200,000 IU of sucrosomial Vit D3 (n=12) or chewable tablet Vit D3 (n=13) for three weeks. In study 2, 20 subjects were randomised to receive a single dose of 200,000 IU every other week of sucrosomial Vit D3 (n=10) or SGC Vit D3 (n=10) for six weeks. Circulatory 25-hydroxyvitamin D3 (25(OH)D) levels were reassessed after two, three and six weeks in study 1, and four-and six weeks in study 2.In study 1, after two weeks, circulatory 25(OH)D levels increased significantly in both Vit D3 groups (p < 0.0001) but improved markedly in sucrosomial group, with no further considerable change after three-and six-weeks in both groups. Overall, at all three follow-ups sucrosomial Vit D3 achieved significantly higher and sustained 25(OH)D levels (p < 0.001). In study 2 after four-weeks, both Vit D3 treatment groups showed significant improvement in 25(OH) levels (p < 0.0001) but substantially higher in sucrosomial group with statistically significant difference between the two groups (p = 0.02). At six-weeks follow-up, only subjects in sucrosomial Vit D3 group showed a further increase in 25(OH)D levels (p = 0.049), but no further significant changes in levels of SGC Vit D3 group (p = 0.062), showing statistically significant difference between the two groups (p = 0.002). The Vit D3 treatment was well tolerated by all participants and no treatment-emergent effects or serious adverse events were reported.Our results suggest that the sucrosomial Vit D3 preparation absorbs efficiently in the GI system, achieving adequately higher and sustained circulatory Vit D levels in VDD, and thus can effectively contribute to protection against VDD-associated health conditions.
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Background: Role of TC2N in carcinogenesis has been largely unfathomed until recently when it was identified as a novel oncogene in lung cancer. Subsequently, a tumour suppressor role of TC2N was reported in breast cancer. It is t...
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Background: Role of TC2N in carcinogenesis has been largely unfathomed until recently when it was identified as a novel oncogene in lung cancer. Subsequently, a tumour suppressor role of TC2N was reported in breast cancer. It is therefore highly relevant to investigate TC2N molecular partners/mechanisms on a larger scale including a wider range of tumour types. Methods: We investigated TC2N mRNA expression, its promoter methylation levels, effects of TC2N transcription on overall patient survival, somatic mutations in TC2N gene and correlation between TC2N mRNA expression and other cancer genes in pan-cancer by using data available from the Cancer Genome Atlas (TCGA) and the Genotype Tissue Expression (GTEx) databases. Results: TC2N mRNA expression was differentially regulated in 9/33 TCGA tumour types. Of these 9 tumours, 5 tumour types (cholangiocarcinoma, ovarian-serous-cystadenocarcinoma, rectal-adenocarcinoma, stomach-adenocarcinoma and thymoma) had significantly higher TC2N mRNA expression while 4 (pheochromocytoma-and-paraganglioma, skin-cutaneous-melanoma, thyroid-carcinoma and uterine-carcinosarcoma) had significantly lower TC2N mRNA expression compared to matched and normal controls. TC2N promoter was hypermethylated in most cancers while hypomethylated in head-and-neck-squamous-cell-carcinoma and kidney-renal-clear-cell carcinoma. TC2N transcription was positively correlated with transcription of several other cancer genes including genes from Myc, cell-cycle, Nrf2, Wnt, PI3K, Hippo, Notch, TGFβ and RAS/RTK pathways. Poor prognosis was associated with higher TC2N mRNA levels in pancreatic-adenocarcinoma and brain-lower-grade-glioma and lower TC2N mRNA levels in kidney-renal-clear-cell-carcinoma, mesothelioma, sarcoma and skin-cutaneous melanoma. Functional protein partners of TC2N were identified as STX2, SMEK1, SMEK2, STXBP5, SCARA5, MMRN1, CATSPER2, CATSPERB, CLEC4M and STAB2. Many of these proteins are key players in carcinogenesis of various cancers. Highest pathogenic somatic mutation rates in TC2N were found in skin-cutaneous-melanoma, uterine-corpus-endometrial-carcinoma, colon-endocervical-adenocarcinoma, bladder-urothelial-carcinoma and breast-invasive-carcinoma. Conclusion: Our findings unravel several un-explored avenues related to the role of TC2N in tumourigenesis of several cancers, suggesting TC2N as an important player and a potential candidate for tumour-therapy.
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The ADPs (ADPs = atomic anisotropic displacement parameters) from the single-crystal X-ray studies of nine related TBA~+ (TBA~+ = (tert-butyl)ammonium) hemispheraplexes are analyzed, and the results compared to the free energy of ...
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The ADPs (ADPs = atomic anisotropic displacement parameters) from the single-crystal X-ray studies of nine related TBA~+ (TBA~+ = (tert-butyl)ammonium) hemispheraplexes are analyzed, and the results compared to the free energy of binding of this guest by the nine hosts. The lipophilic hosts (Fig. 1) were synthesized over a number of years, with increasing pre-organization for and specificity of binding. Structural studies for six of the complexes have been published, but the remaining three structures, including those of the strongest binders of TBA~+, are disordered and have only now been completed. New area-detector data has been analyzed for the TBA~+ClO_4~- complexes of 5 and of 8 at two temperatures, while the original data for 9·TBA~+SCN~- has been treated with a disorder model. In addition, improved models are presented for the complexes of 6 and 7. Methods for assessing the precision of the ADP analyses are discussed. Although most of the structures are imprecise, the TBA~+ groups do demonstrate some of the characteristics of independent motion. The general trend in calculated libration amplitudes for the TBA~+ group suggests that the guests with the greatest free energy of binding, and the shortest distances from N~+ to the ligand plane, are those with the highest barriers to internal rotation.
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Oral squamous cell carcinoma (OSCC) is the most common cancer in Pakistani men and the second most common cancer in women. The objective of our study was to devise a novel accelerated murine model of oral carcinogenesis that can b...
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Oral squamous cell carcinoma (OSCC) is the most common cancer in Pakistani men and the second most common cancer in women. The objective of our study was to devise a novel accelerated murine model of oral carcinogenesis that can be exploited as a tool to investigate the cancer circuitry involved in OSCC and to identify molecules of diagnostic, therapeutic and prognostic significance. A total of 40 healthy male, 6-8 weeks old, 22 ± 2 gram, Naval Medical Research Institute (NMRI) outbred strain mice were recruited in the experiment. NMRI mice are commonly used for animal experiments in various fields of biology and for drug toxicity. Of these, 25 mice underwent the oral carcinogenesis regimen via topical application of 0.5% 9,10-dimethyl-1,2-benzanthracene (DMBA) on the lower left lip for a maximum of 20 weeks and 15 mice were used as controls (without the carcinogenic regimen). Exophytic tissue masses were harvested, fixed in 10% formalin and stained with haematoxylin and eosin (H&E) for microscopic diagnosis. Additionally, the expression levels of CK 5/6, p53 and Ki-67 were investigated using immunohistochemistry. Of the 25 mice which underwent the carcinogenic regimen, 21 developed moderately differentiated squamous cell carcinoma and 1 showed dysplastic features with foci of invasion. Three mice were found dead with lesion(s). CK 5/6 showed strong positivity (100%) and p53 and Ki-67 showed patchy (<30%) strong positivity in OSCC, suggesting the similarity of our model to human OSCC. We present an accelerated, close-to-human carcinogenesis, model of oral carcinogenesis using DMBA in NMRI mice that can be exploited to study the pathogenesis of oral squamous cell carcinoma and subsequently devise immunotherapy or targeted therapy. ? the authors; licensee ecancermedicalscience.
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Superconducting optoelectronic hardware could be used to create large-scale and computationally powerful artificial spiking neural networks. The approach combines integrated photonic components that offer few-photon, light-speed c...
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Superconducting optoelectronic hardware could be used to create large-scale and computationally powerful artificial spiking neural networks. The approach combines integrated photonic components that offer few-photon, light-speed communication with superconducting circuits that offer fast, energy-efficient computation. However, the monolithic integration of photonic and superconducting devices is needed to scale this technology. Here we report superconducting optoelectronic synapses that are created by monolithically integrating superconducting nanowire single-photon detectors with Josephson junctions. The circuits perform analogue weighting and the temporal leaky integration of single-photon presynaptic signals. Synaptic weighting is implemented in the electronic domain allowing binary, single-photon communication to be maintained. Records of recent synaptic activity are locally stored as current in superconducting loops, and dendritic and neuronal nonlinearities are implemented with a second stage of Josephson circuitry. This hardware offers synaptic time constants spanning four orders of magnitude (hundreds of nanoseconds to milliseconds). The synapses are responsive to presynaptic spike rates exceeding 10 MHz and consume approximately 33 aJ of dynamic power per synapse event before accounting for cooling. This demonstration also introduces new avenues for realizing large-scale single-photon detector arrays.
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Background:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing global pandemic known as COVID-19. Based on the potential antiviral role of quercetin, and on its described anti-blood clottin...
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Background:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing global pandemic known as COVID-19. Based on the potential antiviral role of quercetin, and on its described anti-blood clotting, anti-inflammatory and antioxidant properties, we hypothesize that subjects with mild COVID-19 treated with Quercetin Phytosome<sup>?</sup> (QP), a novel bioavailable form of quercetin, may have a shorter time to virus clearance, a milder symptomatology, and higher probabilities of a benign earlier resolution of the disease.Methods:In our 2-week, randomized, open-label, and controlled clinical study, we have enrolled 42 COVID-19 outpatients. Twenty-one have been treated with the standard of care (SC), and 21 with QP as add-on supplementation to the SC. Our main aims were to check virus clearance and symptoms.Results:The interim results reveal that after 1 week of treatment, 16 patients of the QP group were tested negative for SARS-CoV-2 and 12 patients had all their symptoms diminished; in the SC group, 2 patients were tested SARS-CoV-2 negative and 4 patients had their symptoms partially improved. By 2 weeks, the remaining 5 patients of the QP group tested negative for SARS-CoV-2, whereas in the SC group out of 19 remaining patients, 17 tested negatives by week 2, one tested negative by week 3 and one patient, still positive, expired by day 20. Concerning blood parameters, the add on therapy with QP, reduced LDH (-35.5%), Ferritin (-40%), CRP (-54.8%) and D-dimer (-11.9%).Conclusion:QP statistically shortens the timing of molecular test conversion from positive to negative, reducing at the same time symptoms severity and negative predictors of COVID-19.
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Samples of 4,40-bis(3,3,3-tri-d5-phenylpropynyl)biphenyl 2, 9,10-bis(3,3,3-tri-d5-phenylpropynyl)- anthracene 3, 1,4-bis(3,3,3-tri-d5-phenylpropynyl)naphthalene 4, and 4,40-bis(3,3,3-tri-d5-phenylpropynyl)- 1,10-binaphthyl 5 were ...
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Samples of 4,40-bis(3,3,3-tri-d5-phenylpropynyl)biphenyl 2, 9,10-bis(3,3,3-tri-d5-phenylpropynyl)- anthracene 3, 1,4-bis(3,3,3-tri-d5-phenylpropynyl)naphthalene 4, and 4,40-bis(3,3,3-tri-d5-phenylpropynyl)- 1,10-binaphthyl 5 were prepared via a Sonogashira coupling of 3,3,3-tri-d5-phenylpropyne 7 and the appropriate aryl dibromide. Single crystal X-ray diffraction structures were obtained for an o-xylene clathrate of 2 and for solvent-free crystals of 3. All four molecular rotors were characterized by CPMAS 13C NMR experiments with varying contact times in order to determine whether the carbon signals of the central rotator group could be selectively enhanced and studied without interference or overlap of signals from the deuterated stator, which is insensitive to the {1H}-13C cross-polarization method. It was shown that the 13C signals of the natural abundance rotator group can be selectively observed with short contact times (ca. 50 μs) without interference from other 13C signals in the molecule. Variable-temperature CPMAS 13C NMR studies with a crystalline o-xylene solvate of biphenylene rotor 2 suggested a 2-fold flipping process in the fast exchange regime, even at temperatures as low as 199 K (-74 C). Indirect support for this was obtained by studies carried out with a disordered, solvent-free solid, obtained by fast precipitation from hexanes and dichloromethane, which displayed slower dynamics within the same temperature range with an activation energy of 8.7 kcal/mol and a pre-exponential factor of 4.9 109 s-1. Confirmation of an exchange process in the megahertz regime for the crystalline solvate was obtained by variable-temperature quadrupolar echo 2H NMR data acquired with samples prepared with a deuterated biphenylene rotator and a natural abundance stator. Although rotational exchange occurs in the solvated samples with a slightly lower barrier of 7.4 kcal/mol, the main difference with the precipitated solid comes from the pre-exponential factor, which is nearly 3 orders of magnitude greater with a value of 2.5 1012 s-1. On the basis of these differences, we speculate that efficient rotational motion in the solvated crystals may take advantage of long-range lattice vibrations that couple with molecular modes and that the lack of long-range order may be responsible for the low pre-exponential factor observed in the disordered crystals.
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In this study, we compared the efficiency of culture-based methods with or without membrane filtration, real-time PCR, and digital droplet PCR (ddPCR) for the detection of Campylobacter in fresh produce. Alfalfa sprouts, clover sp...
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In this study, we compared the efficiency of culture-based methods with or without membrane filtration, real-time PCR, and digital droplet PCR (ddPCR) for the detection of Campylobacter in fresh produce. Alfalfa sprouts, clover sprouts, coleslaw, and lettuce salad spiked with Campylobacter jejuni were enriched in Bolton broth for 48 h, and enrichment cultures were either directly inoculated onto modified charcoal-cefoperazone-deoxycholate agar or applied on membrane filters placed on the surface of plating media. In parallel, 2-mL Bolton broth cultures were taken to extract DNA for real-time PCR and ddPCR assays and bacterial community analysis. A developed primer set for ddPCR and real-time PCR was evaluated for its inclusivity and exclusivity using pure culture of C. jejuni and non-C. jejuni strains, respectively. In pure culture, the primer set reacted only with C. jejuni strains and showed negative reaction to non-C. jejuni strains. There was no significant difference (P > 0.05) in the detection efficiency of positive Campylobacter isolates from coleslaw and lettuce salad using four detection methods. However, for sprout samples, the detection efficiency of the culture method was significantly (P < 0.05) lower than those of the two PCR assays and the filtration method. The analysis also revealed the presence of Pseudomonas and Acinetobacter as the most prevalent competing microbiota in enriched culture and only Acinetobacter on agar plates in the selective culture step.
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