For
(
A
,
m
)
a local ring, we study the natural map from the Koszul cohomology module
H
dim
A
(
m
;
A
)
to the local cohomology module
H
m
dim
A
(
A
)
. We prove that the injectivity of this map ...characterizes the Cohen-Macaulay property of the ring
A
. We also answer a question of Dutta by constructing normal rings
A
for which this map is zero.
Human and rodent solid tumors often exhibit elevated interstitial fluid pressure (IFP). This condition is recognized as a prognostic indicator for reduced responses to therapy and decreased ...disease-free survival rate. In the present study, we tested whether induction of a thermoregulatory-mediated increase in tissue blood flow, induced by exposure of mice to mild environmental heat stress, could influence IFP and other vascular parameters within tumors. Using several murine tumor models, we found that heating results in a sustained reduction in tumor IFP correlating with increased tumor vascular perfusion (measured by fluorescent imaging of perfused vessels, laser Doppler flowmetry, and MRI) as well as a sustained reduction in tumor hypoxia. Furthermore, when radiation therapy was administered 24 hours postheating, we observed a significant improvement in efficacy that may be a result of the sustained reduction in tumor hypoxia. These data suggest, for the first time, that environmental manipulation of normal vasomotor function is capable of achieving therapeutically beneficial changes in IFP and microvascular function in the tumor microenvironment.
With the rapid growth of deep learning research for medical applications comes the need for clinical personnel to be comfortable and familiar with these techniques. Taking a proven approach, we ...developed a straightforward open-source framework for producing automatic contours for head and neck planning computed tomography studies using a convolutional neural network (CNN).
Anonymized studies of 229 patients treated at our clinic for head and neck cancer from 2014 to 2018 were used to train and validate the network. We trained a separate CNN iteration for each of 11 common organs at risk, and then used data from 19 patients previously set aside as test cases for evaluation. We used a commercial atlas-based automatic contouring tool as a comparative benchmark on these test cases to ensure acceptable CNN performance. For the CNN contours and the atlas-based contours, performance was measured using three quantitative metrics and physician reviews using survey and quantifiable correction time for each contour.
The CNN achieved statistically better scores than the atlas-based workflow on the quantitative metrics for 7 of the 11 organs at risk. In the physician review, the CNN contours were more likely to need minor corrections but less likely to need substantial corrections, and the cumulative correction time required was less than for the atlas-based contours for all but two test cases.
With this validation, we packaged the code framework and trained CNN parameters and a no-code, browser-based interface to facilitate reproducibility and expansion of the work. All scripts and files are available in a public GitHub repository and are ready for immediate use under the MIT license. Our work introduces a deep learning tool for automatic contouring that is easy for novice personnel to use.
Aim
SLC26A3 (DRA) mediates the absorption of luminal Cl− in exchange for HCO3− in the distal intestine. Its expression is lost in congenital chloride diarrhoea (CLD) and strongly decreased in the ...presence of intestinal inflammation. To characterize the consequences of a loss of Slc26a3 beyond disturbed electrolyte transport, colonic mucus synthesis, surface accumulation and composition, pH microclimate, microbiome composition and development of inflammation was studied in slc26a3−/− mice.
Methods
The epithelial surface pH microclimate and the surface mucus accumulation in vivo was assessed by two photon microscopy in exteriorized mid colon of anaesthetized slc26a3−/− and wt littermates. Mucus synthesis, composition and inflammatory markers were studied by qPCR and immunohistochemistry and microbiome composition by 16S rRNA sequencing.
Results
Colonic pH microclimate was significantly more acidic in slc26a3−/− and to a lesser extent in cftr−/− than in wt mice. Goblet cell thecae per crypt were decreased in slc26a3−/− and increased in cftr−/− colon. Mucus accumulation in vivo was reduced, but much less so than in cftr−/− colon, which is possibly related to the different colonic fluid balance. Slc26a3−/− colonic luminal microbiome displayed strong decrease in diversity. These alterations preceded and maybe causally related to increased mucosal TNFα mRNA expression levels and leucocyte infiltration in the mid‐distal colon of slc26a3−/− but not of cftr−/− mice.
Conclusions
These findings may explain the strong increase in the susceptibility of slc26a3−/− mice to DSS damage, and offer insight into the mechanisms leading to an increased incidence of intestinal inflammation in CLD patients.
While stereotactic body radiotherapy (SBRT) can reduce tumor volumes in patients with metastatic renal cell carcinoma (mRCC), little is known regarding the immunomodulatory effects of high-dose ...radiation in the tumor microenvironment. The main objectives of this pilot study were to assess the safety and feasibility of nephrectomy following SBRT treatment of patients with mRCC and analyze the immunological impact of high-dose radiation.
Human RCC cell lines were irradiated and evaluated for immunomodulation. In a single-arm feasibility study, patients with mRCC were treated with 15 Gray SBRT at the primary lesion in a single fraction followed 4 weeks later by cytoreductive nephrectomy. RCC specimens were analyzed for tumor-associated antigen (TAA) expression and T-cell infiltration. The trial has reached accrual (ClinicalTrials.gov identifier: NCT01892930).
RCC cells treated
with radiation had increased TAA expression compared with untreated tumor cells. Fourteen patients received SBRT followed by surgery, and treatment was well-tolerated. SBRT-treated tumors had increased expression of the immunomodulatory molecule calreticulin and TAA (CA9, 5T4, NY-ESO-1, and MUC-1). Ki67
-proliferating CD8
T cells and FOXP3
cells were increased in SBRT-treated patient specimens in tumors and at the tumor-stromal interface compared with archived patient specimens.
It is feasible to perform nephrectomy following SBRT with acceptable toxicity. Following SBRT, patient RCC tumors have increased expression of calreticulin, TAA, as well as a higher percentage of proliferating T cells compared with archived RCC tumors. Collectively, these studies provide evidence of immunomodulation following SBRT in mRCC.
.
While immunotherapy in cancer is designed to stimulate effector T cell response, tumor-associated antigens have to be presented on malignant cells at a sufficient level for recognition of cancer by T ...cells. Recent studies suggest that radiotherapy enhances the anti-cancer immune response and also improves the efficacy of immunotherapy. To understand the molecular basis of such observations, we examined the effect of ionizing X-rays on tumor antigens and their presentation in a set of nine human cell lines representing cancers of the esophagus, lung, and head and neck. A single dose of 7.5 or 15 Gy radiation enhanced the New York esophageal squamous cell carcinoma 1 (NY-ESO-1) tumor-antigen-mediated recognition of cancer cells by NY-ESO-1-specific CD8
T cells. Irradiation led to significant enlargement of live cells after four days, and microscopy and flow cytometry revealed multinucleation and polyploidy in the cells because of dysregulated mitosis, which was also revealed in RNA-sequencing-based transcriptome profiles of cells. Transcriptome analyses also showed that while radiation had no universal effect on genes encoding tumor antigens, it upregulated the expression of numerous genes involved in antigen processing and presentation pathways in all cell lines. This effect may explain the immunostimulatory role of cancer radiotherapy.
IMPORTANCE: Oral mucositis causes substantial morbidity during head and neck radiotherapy. In a randomized study, doxepin mouthwash was shown to reduce oral mucositis–related pain. A common mouthwash ...comprising diphenhydramine-lidocaine-antacid is also widely used. OBJECTIVE: To evaluate the effect of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash for the treatment of oral mucositis–related pain. DESIGN, SETTING, AND PARTICIPANTS: A phase 3 randomized trial was conducted from November 1, 2014, to May 16, 2016, at 30 US institutions and included 275 patients who underwent definitive head and neck radiotherapy, had an oral mucositis pain score of 4 points or greater (scale, 0-10), and were followed up for a maximum of 28 days. INTERVENTIONS: Ninety-two patients were randomized to doxepin mouthwash (25 mg/5 mL water); 91 patients to diphenhydramine-lidocaine-antacid; and 92 patients to placebo. MAIN OUTCOME AND MEASURES: The primary end point was total oral mucositis pain reduction (defined by the area under the curve and adjusted for baseline pain score) during the 4 hours after a single dose of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash compared with a single dose of placebo. The minimal clinically important difference was a 3.5-point change. The secondary end points included drowsiness, unpleasant taste, and stinging or burning. All scales ranged from 0 (best) to 10 (worst). RESULTS: Among the 275 patients randomized (median age, 61 years; 58 21% women), 227 (83%) completed treatment per protocol. Mucositis pain during the first 4 hours decreased by 11.6 points in the doxepin mouthwash group, by 11.7 points in the diphenhydramine-lidocaine-antacid mouthwash group, and by 8.7 points in the placebo group. The between-group difference was 2.9 points (95% CI, 0.2-6.0; P = .02) for doxepin mouthwash vs placebo and 3.0 points (95% CI, 0.1-5.9; P = .004) for diphenhydramine-lidocaine-antacid mouthwash vs placebo. More drowsiness was reported with doxepin mouthwash vs placebo (by 1.5 points 95% CI, 0-4.0; P = .03), unpleasant taste (by 1.5 points 95% CI, 0-3.0; P = .002), and stinging or burning (by 4.0 points 95% CI, 2.5-5.0; P < .001). Maximum grade 3 adverse events for the doxepin mouthwash occurred in 3 patients (4%); diphenhydramine-lidocaine-antacid mouthwash, 3 (4%); and placebo, 2 (2%). Fatigue was reported by 5 patients (6%) in the doxepin mouthwash group and no patients in the diphenhydramine-lidocaine-antacid mouthwash group. CONCLUSIONS AND RELEVANCE: Among patients undergoing head and neck radiotherapy, the use of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash vs placebo significantly reduced oral mucositis pain during the first 4 hours after administration; however, the effect size was less than the minimal clinically important difference. Further research is needed to assess longer-term efficacy and safety for both mouthwashes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02229539
We conducted a systematic review and meta-analysis to evaluate outcomes after allogeneic hematopoietic stem cell transplantation (HSCT) in TP53-mutated acute myeloid leukemia (AML). We performed a ...literature search on PubMed, Embase, Cochrane Library, and ClinicalTrials.gov. After screening 592 manuscripts, eight studies were included. Data were extracted following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Pooled analysis was done using the meta-package by Schwarzer et al. Proportions with 95% confidence intervals (CIs) were computed. We analyzed 297 patients. The median follow-up was 45 (0.9-407.3) months. The pooled 2-year overall survival was 29.7% (95% CI 0.17-0.43, n = 82/248). The pooled relapse rate was 61.4% (95% CI 0.41-0.79, n = 139/247) at a median follow-up time of 2 (0.26-3) years. Three-year progression-free survival and non-relapse mortality were reported by one study as 7.5% and 32.5%, respectively. Outcomes of HSCT for TP53-mutated AML are poor; however, HSCT confers a survival advantage as compared to non-transplant palliative therapies.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Consider a reductive linear algebraic group G acting linearly on a polynomial ring S over an infinite field; key examples are the general linear group, the symplectic group, the orthogonal group, and ...the special linear group, with the classical representations as in Weyl’s book: For the general linear group, consider a direct sum of copies of the standard representation and copies of the dual; in the other cases, take copies of the standard representation. The invariant rings in the respective cases are determinantal rings, rings defined by Pfaffians of alternating matrices, symmetric determinantal rings and the Plücker coordinate rings of Grassmannians; these are the classical invariant rings of the title, with
$S^G\subseteq S$
being the natural embedding. Over a field of characteristic zero, a reductive group is linearly reductive, and it follows that the invariant ring
$S^G$
is a pure subring of S, equivalently,
$S^G$
is a direct summand of S as an
$S^G$
-module. Over fields of positive characteristic, reductive groups are typically no longer linearly reductive. We determine, in the positive characteristic case, precisely when the inclusion
$S^G\subseteq S$
is pure. It turns out that if
$S^G\subseteq S$
is pure, then either the invariant ring
$S^G$
is regular or the group G is linearly reductive.
Xerostomia, or dry mouth, is a significant problem affecting quality of life in patients treated with radiation therapy for head and neck cancer. Strategies for reduction of xerostomia burden vary ...widely, with options including: sialagogue medications, saliva substitutes, acupuncture, vitamins, hyperbaric oxygen, submandibular gland transfer, and acupuncture or associated treatments. In this review, we sought to evaluate long-term outcomes of patients treated with various interventions for radiation-induced xerostomia. A literature search was performed using the terms "xerostomia" and "radiation" or "radiotherapy"; all prospective clinical trials were evaluated, and only studies that reported 1 year follow up were included. The search results yielded 2193 studies, 1977 of which were in English. Of those, 304 were clinical trials or clinical studies. After abstract review, 23 trials were included in the review evaluating the following treatment modalities: pilocarpine (three); cevimeline (one); amifostine (eleven); submandibular gland transfer (five); acupuncture like transcutaneous electrical nerve stimulation (ALTENS) (one); hyperbaric oxygen (one); and acupuncture (one). Pilocarpine, cevimeline, and amifostine have been shown in some studies to improve xerostomia outcomes, at the cost of toxicity. ALTENS has similar efficacy with fewer side effects. Submandibular gland transfer is effective but requires an elective surgery, and thus may not always be appropriate or practical. The use of intensity-modulated radiation therapy, in addition to dose de-escalation in select patients, may result in fewer patients with late xerostomia, reducing the need for additional interventions.
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