The addition of amifostine to chemoradiotherapy (CRT) or radiotherapy (RT) in advanced, inoperable NSCLC presents varying toxicity. The present study examined amifostine's effect on toxicity and ...efficacy of CRT or RT alone.
Database searches yielded 16 eligible trials comprising of 1,057 patients. Results of randomised trials were pooled and used to estimate the overall effect.
Amifostine reduced the risk of >grade 2 acute oesophagitis by 26% risk ratio (RR), 0.74; 95% confidence interval (CI)=0.65-0.86; p<0.0001 and the risk of acute pulmonary toxicity by 44% (RR, 0.56; 95%CI=0.41-0.75; p=0.0001). Risk of complete response was unchanged (RR, 1.64; 95%CI=0.99-2.73; p=0.06), partial response was unchanged (RR, 0.92; 95% CI=0.73-1.16; p=0.48). Statistical heterogeneity was high for toxicity but low for response.
Statistical heterogeneity of retrived results casts doubt over amifostine's efficacy in this setting, despite decreased acute oesophageal and pulmonary toxicity. Amifostine did not compromise treatment efficacy.
•Low ORN incidence 4.4% (47/1,050)•Increased risk ORN with mandibular surgery.•Complete ORN resolution in 17% of patients.•Opportunities for risk reduction identified.•Intensive lifelong dental care ...essential.
To assess osteoradionecrosis (ORN) incidence in a population of Irish Head and Neck cancer (HNC) patients, and assess precipitating factors that may contribute to ORN development to aid prevention.
Review of 1050 HNC patients attending the Dental Oncology Clinic, CUDSH between 2010 and 2021 identified 47 cases of ORN. Medical, dental and radiotherapy records of these forty-seven patients were retrospectively reviewed. Patient-, tumour-, and treatment-related variables were investigated in association with osteoradionecrosis development. Analysis conducted using SPSS, Pearson’s Chi-square test (p < 0.05), and ordinal regression model.
ORN incidence was 4.4 %. Median time from radiotherapy (RT) to ORN development was 9.5 months (range 1–98.5 months). ORN development within the mandibular surgical site was significant (p <.001), presenting at a higher Notani grade (p =.002), in mid-mandibular body region (p =.028), at radiation doses ≥ 60 Gy (p =.035), due to induced causes (p =.029), and without resolution (p =.019).
This is the first retrospective study of ORN in HNC patients in Ireland over 10-year period. ORN incidence was extremely low (4.4%). As patients reported high smoking/alcohol use and poor dental attendance pre-diagnosis, this suggests intensive dental intervention pre/post-diagnosis contributed to low ORN rates. Mandibular surgery pre-RT increased risk of developing ORN at the surgical site. Therefore, we recommend future treatment planning should contour the surgical site, designating it an organ at risk (OAR), assigning a dose constraint, where oncologically possible, with emphasis on reducing the hot-spot to this region; findings reinforce importance of life-long expert dental care to reduce ORN incidence.
The incomplete identification of structural variants (SVs) from whole-genome sequencing data limits studies of human genetic diversity and disease association. Here, we apply a suite of long-read, ...short-read, strand-specific sequencing technologies, optical mapping, and variant discovery algorithms to comprehensively analyze three trios to define the full spectrum of human genetic variation in a haplotype-resolved manner. We identify 818,054 indel variants (<50 bp) and 27,622 SVs (≥50 bp) per genome. We also discover 156 inversions per genome and 58 of the inversions intersect with the critical regions of recurrent microdeletion and microduplication syndromes. Taken together, our SV callsets represent a three to sevenfold increase in SV detection compared to most standard high-throughput sequencing studies, including those from the 1000 Genomes Project. The methods and the dataset presented serve as a gold standard for the scientific community allowing us to make recommendations for maximizing structural variation sensitivity for future genome sequencing studies.
Bushfire smoke contains an array of organic and inorganic compounds, including respirable and inspirable particles, aldehydes, and carbon monoxide. These compounds have been found to be a health ...hazard for firefighters in the United States. Despite the high frequency of bushfires in Australia, analyses of bushfire smoke components are scarce. As part of an occupational health study investigating the respiratory health effects of bushfire smoke in firefighters, air toxics sampling was undertaken in a smoke chamber and during prescribed burns. Levels of formaldehyde and acrolein were demonstrated at respectively 60% and 80% of the Short Term Exposure Limit in the smoke chamber. Carbon monoxide levels exceeded the peak limit of 400 ppm significantly. Although concentrations were lower during the prescribed burns, the study shows that Australian bushfire smoke contains air toxics of concern and provides justification for further research into the levels of air toxics measured at bushfires and the associated health impacts.
Short tandem repeats (STRs) and variable number tandem repeats (VNTRs) are important sources of natural and disease-causing variation, yet they have been problematic to resolve in reference genomes ...and genotype with short-read technology. We created a framework tomodel the evolution and instability of STRs and VNTRs in apes. We phased and assembled 3 ape genomes (chimpanzee, gorilla, and orangutan) using long-read and 10x Genomics linkedread sequence data for 21,442 human tandem repeats discovered in 6 haplotype-resolved assemblies of Yoruban, Chinese, and Puerto Rican origin. We define a set of 1,584 STRs/VNTRs expanded specifically in humans, including large tandem repeats affecting coding and noncoding portions of genes (e.g., MUC3A, CACNA1C). We show that short interspersed nuclear element–VNTR–Alu (SVA) retrotransposition is the main mechanism for distributing GC-rich human-specific tandem repeat expansions throughout the genome but with a bias against genes. In contrast, we observe that VNTRs not originating from retrotransposons have a propensity to cluster near genes, especially in the subtelomere. Using tissuespecific expression from human and chimpanzee brains, we identify genes where transcript isoform usage differs significantly, likely caused by cryptic splicing variation within VNTRs. Using single-cell expression from cerebral organoids, we observe a strong effect for genes associated with transcription profiles analogous to intermediate progenitor cells. Finally, we compare the sequence composition of some of the largest human-specific repeat expansions and identify 52 STRs/VNTRs with at least 40 uninterrupted pure tracts as candidates for genetically unstable regions associated with disease.
The human bone marrow contains mesenchymal stem cells capable of differentiating along multiple mesenchymal cell lineages. Using a non-human primate model, we sought to determine whether the systemic ...infusion of baboon-derived mesenchymal stem cells was associated with toxicity and whether these cells were capable of homing to and persisting within the bone marrow.
Five baboons (
Papio anubis) were administered lethal irradiation followed by intravenous autologous hematopoietic progenitor cells combined with either autologous
(
n
= 3)
or allogeneic
(
n
= 2)
mesenchymal stem cells that had been expanded in culture. In four of these baboons, the mesenchymal stem cells were genetically modified with a retroviral vector encoding either the enhanced green fluorescent protein gene
(
n
= 3)
or the human placental alkaline phosphatase gene
(
n
= 1)
for tracking purposes. A sixth animal received only intravenous gene marked autologous mesenchymal stem cells but no hematopoietic stem cells or conditioning irradiation.
Following culture, baboon mesenchymal stem cells appeared morphologically as a homogeneous population of spindle-shaped cells that were identified by the monoclonal antibodies SH-3 and SH-4. These cells did not express the hematopoietic markers CD34 or CD45. Baboon mesenchymal stem cells isolated from primary culture were capable of differentiating along both adipogenic and osteogenic lineages. There was no acute or chronic toxicity associated with the intravenous infusion of mesenchymal stem cells. In all five recipients of gene marked mesenchymal stem cells, transgene was detected in post-transplant bone marrow biopsies. In two animals receiving autologous mesenchymal stem cells, including the one non-conditioned recipient, transgene could be detected over 1 year following infusion. In one recipient of allogeneic gene marked mesenchymal stem cells, transgene was detected in the bone marrow at 76 days following infusion.
These data demonstrate that baboon mesenchymal stem cells: 1) are not associated with significant toxicity when administered intravenously, 2) are capable of homing to the bone marrow following intravenous infusion, and 3) have the capacity to establish residence within the bone marrow for an extended duration following systemic administration.
Mesenchymal stem cells (MSCs), multipotential cells that reside within the bone marrow, can be induced to differentiate into various components of the marrow microenvironment, such as bone, adipose, ...and stromal tissues. The bone marrow microenvironment is vital to the development, differentiation, and regulation of the lymphohematopoietic system. We hypothesized that the activities of MSCs in the bone marrow microenvironment might also include immunomodulatory effects on lymphocytes.
Baboon MSCs were tested in vitro for their ability to elicit a proliferative response from allogeneic lymphocytes, to inhibit an ongoing allogeneic response, and to inhibit a proliferative response to potent T-cell mitogens. In vivo effects were tested by intravenous administration of donor MSCs to MHC-mismatched recipient baboons prior to placement of autologous, donor, and third-party skin grafts.
MSCs failed to elicit a proliferative response from allogeneic lymphocytes. MSCs added into a mixed lymphocyte reaction, either on day 0 or on day 3, or to mitogen-stimulated lymphocytes, led to a greater than 50% reduction in proliferative activity. This effect could be maximized by escalating the dose of MSCs and could be reduced with the addition of exogenous IL-2. In vivo administration of MSCs led to prolonged skin graft survival when compared to control animals: 11.3 ± 0.3 vs 7 ± 0.
Baboon MSCs have been observed to alter lymphocyte reactivity to allogeneic target cells and tissues. These immunoregulatory features may prove useful in future applications of tissue regeneration and stem cell engineering.
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