Tissue Tolerance Research Articles

Caspofungin formulations for buccal and sublingual mucosae anti-fungal infections: physicochemical characterization, rheological analysis, release and ex vivo permeability profiles

Aim Oral candidiasis is often challenging due to limited effectiveness of topical treatments. This study aimed to develop novel caspofungin formulations for administration onto the oral mucosa to enhance drug retention and efficacy. Method Five caspofungin (2%, w/v) formulations were developed to assess their permeability, retention and mucoadhesiveness. Ex vivo permeability assays were performed on buccal and sublingual mucosae, and histological analyses conducted to evaluate tissue tolerance. Results Formulation composed of chitosan demonstrated the highest retention in both buccal (5183.24 ± 587.32 µg/cm2) and sublingual (1090.72 ± 110.26 µg/cm2) mucosae. Other formulations exhibited significantly lower retention, ranging from 7.53 ± 0.81 to 1852.10 ± 193.24 µg/cm2 in buccal mucosa and 1.64 ± 0.14 to 317.74 ± 31.78 µg/cm2 in sublingual mucosa. Chitosan-based formulation exhibited the highest mucoadhesive strength, with values of 5179.05 ± 31.99 mN/cm2 for buccal and 7026.10 ± 123.41 mN/cm2 for sublingual mucosae, and also superior extensibility, which facilitates application in the oral cavity. All formulations showed antifungal activity against Candida spp., and histological analyses revealed minor epithelial alterations. Conclusion The developed formulations offer distinct advantages for treating oral candidiasis, with chitosan formulation emerging as the most promising due to its superior retention, mucoadhesion force, and spreadability, making it a potential candidate for further clinical investigation.

Evaluating the benefit of contact-force feedback in robotic surgery using the Saroa surgical system: A preclinical study.

Robotic surgery without contact-force feedback could be less safe, as forces exerted by the robot system may exceed tissue tolerance. This study aimed to evaluate the benefit of contact-force feedback. Nine junior and 11 senior surgeons performed two tasks using Saroa, a robotic surgical system with a force feedback function. In Task A, the participants estimated the order of stiffness of substances when feedback was on and off. In Task B, the effect of feedback on compression with a designated force (3 N) was assessed. In Task A, the proportion of participants who correctly estimated the order of stiffness of the substances was similar when feedback was on and off. However, the median maximum force applied to the substances was significantly smaller when feedback was on than when it was off (5.0 vs. 6.9 N, p = .011), which was more obvious among the junior surgeons (5.0 vs. 7.7 N, p = .015) than among the senior surgeons (4.7 vs. 5.9 N, p = .288). In Task B, deviations from the designated force (3 N) for three substances were smaller when feedback was on (0, -0.1, and 0.7, respectively) than when it was off (-0.3, -0.5, and 1.3, respectively). Regarding the dispersion of the force to the substances, the interquartile range tended to be smaller with feedback; this trend was more obvious in the junior surgeons. With contact-force feedback, tissue stiffness could be estimated with a small force, particularly by the junior surgeons; specified force could be accurately applied to the tissue.

Assessment of different shielding materials for radiation therapy of maxillofacial tumors – An in vitro study

Aim: Since the advent of radiotherapy, the success rate of head and neck cancer treatment has increased significantly. However, when the tissue tolerance level is exceeded, unnecessary and uncontrolled exposure to radiation is considered detrimental. Such problems remain difficult to prevent and manage. The aim of the study to evaluate and compare the degree of attenuation of therapeutic radiation using four different radiation shielding materials of varying thickness. Study Setting and Design: In vitro experimental study. Materials and Methods: The samples were divided into four groups based on the different radiation shielding materials of thickness 3mm and 5mm. The materials are Lead (Pb), Silver-tin alloy (Ag-Sn) with Polyvinylsiloxane (PVS), Polymethylmethacrylate (PMMA) with Barium sulphate (BaSO4), and a combination of Ag-Sn with PVS and PMMA with BaSO4 which was exposed to radiation. The radiation dose measurements were recorded and the radiation attenuation properties of the shielding materials were evaluated. Among all of the shielding materials the most efficient material under consideration is determined. Statistical Analysis Used: One-way ANOVA followed by post hoc test was used to compare the means of all four groups. Results: A statistically significant difference between groups was found by a one-way ANOVA with a P = 0.001. In the post hoc test, statistically significant findings were obtained with a P = 0.05 when comparing the variation values of 3mm and 5mm thickness between each group and other groups. Conclusion: The shielding materials results in significant reductions in radiation dosage. It was concluded that the combinations of Ag-Sn alloy with PVS, and PMMA with BaSO4 of thickness 5 mm had a good shielding effect.

The SIRT5-Mediated Upregulation of C/EBPβ Promotes White Adipose Tissue Browning by Enhancing UCP1 Signaling.

Sirtuin 5 (SIRT5) plays an important role in the maintenance of lipid metabolism and in white adipose tissue browning. In this study, we established a mouse model for diet-induced obesity and the browning of white fat; combined with gene expression intervention, transcriptome sequencing, and cell molecular biology methods, the regulation and molecular mechanisms of SIRT5 on fat deposition and beige fat formation were studied. The results showed that the loss of SIRT5 in obese mice exacerbated white adipose tissue deposition and metabolic inflexibility. Furthermore, the deletion of SIRT5 in a white-fat-browning mouse increased the succinylation of uncoupling protein 1 (UCP1), resulting in a loss of the beiging capacity of the subcutaneous white adipose tissue and impaired cold tolerance. Mechanistically, the inhibition of SIRT5 results in impaired CCAAT/enhancer binding protein beta (C/EBPβ) expression in brown adipocytes, which in turn reduces the UCP1 transcriptional pathway. Thus, the transcription of UCP1 mediated by the SIRT5-C/EBPβ axis is critical in regulating energy balance and obesity-related metabolism.

Simultaneous integrated boost-intensity modulated radiation therapy (SIBIMRT) planning for pelvic tumours: dose coverage to target volume and normal tissue sparing.

To evaluate the better radiotherapy plan for pelvic tumours that may achieve a high target coverage dose and low normal tissue tolerance dose using simultaneous integrated boost-intensity-modulated radiation therapy technique. The analytical, cross-sectional, descriptive study was conducted from October 2020 to March 2021 at Al- Amal National Hospital for Cancer Treatment, Baghdad, Iraq, and comprised male pelvic cancer patients aged 50-80 years. Computed tomography scans were randomly selected. For each patient, 4 treatment plans (phases Ι and Π) were generated using the simultaneous integrated boost-intensity-modulated radiation therapy technique while keeping all parameters constant except the number of beams, which were 5, 7, 9 and 11. The optimal and safe dose was defined as the one to cover 95% planning target volume. Homogeneity and conformity indices were used to assess the uniformity of dose distribution in the target volume, and various treatment plans in the same patient were compared. Data was analysed using SPSS 24. There were 15 males with mean age 67.12±2.84 years. There was a significant variance in the target volume dose and organ at risk in the 4 different plans generated using the simultaneous integrated boost-intensitymodulated radiation therapy technique (p<0.05). The 9-beam treatment plan was the best for coverage of tumours and protection of healthy organs assessed through homogeneity and conformity indices (p<0.05). The 9-beam treatment plan showed significant tumour coverage, homogeneity and conformity values, and sparing dose for organs at risk.

On the significance of the different geometrical and dosimetric parameters in microbeam and minibeam radiation therapy a retrospective evaluation.

Spatially Fractionated Radiation Therapy (SFRT) is an unconventional therapeutic approach with the potential to disrupt the classical paradigms of conventional radiation therapy. The high spatial dose modulation in SFRT is believed to activate distinct radiobiological mechanisms which lead to remarkable increases in normal tissue tolerance. To make optimal use of SFRT and its benefits, a deeper understanding of the biological response and its relationship with the complex dosimetric and geometric components of SFRT is essential. A retrospective evaluation of preclinical studies was conducted to gain insight into the dosimetric and geometric parameters that are most correlated with normal tissue response. Current literature evaluates the response of tissue to MBRT and MRT according to various end points, e.g. the level of desquamation, degree of necrosis, or the amount of malcalcification. A set of metrics was developed to allow a quantitative comparison of these results. The strongest correlations were observed with the doses in both the peaks and valleys as well as the ratio of the area covered by the peak over the total area. This emphasises the geometry of the beam. MBRT challenged previous uniform dose-distribution paradigms by highlighting the critical role of Peak Dose alongside Valley Dose in tissue sparing whereas MRT underscores the significant influence of geometric beam parameters on tissue preservation. The data exhibits variability in the results obtained using different animal models and endpoints and additional research is warranted to explore the trends observed in this study under controlled conditions.

Moving beyond mean heart dose: The importance of cardiac substructures in radiation therapy toxicity.

Normal tissue tolerance dose limits to the heart have been established to reduce the risk of radiation-induced cardiac disease (RICD). Dose constraints have been developed based on either the mean dose delivered to the whole heart (MHD) or the dose delivered to a specific volume, for example, volume of heart receiving equal to or greater than 30 Gy (V30). There is increasing evidence that the impact of thoracic radiation on cardiac morbidity and mortality has been underestimated. Consequently, there is a need to reduce the dose delivered to the heart in radical radiotherapy treatment planning. The pathophysiology of RICD may relate to dose to specific cardiac substructures (CS) rather than the traditionally observed MHD for common toxicities. The MHD or V30 Gy threshold dose rarely represents the true dose delivered to individual CS. Studies have shown the dose to specific areas may be more strongly correlated with overall survival (OS). With advances in modern radiotherapy techniques, it is vital that we develop robust, evidence-based dose limits for CS, to fully understand and reduce the risk of RICD, particularly in high-risk populations with cardiac risk factors. The following review will summarise the existing evidence of dose limits to CS, explain how dose limits may vary according to different disease sites or radiation techniques and propose how radiotherapy plans can be optimised to reduce the dose to these CS in clinical practice.

Salt tolerance in mungbean is associated with controlling Na and Cl transport across roots, regulating Na and Cl accumulation in chloroplasts and maintaining high K in root and leaf mesophyll cells.

Salinity tolerance requires coordinated responses encompassing salt exclusion in roots and tissue/cellular compartmentation of salt in leaves. We investigated the possible control points for salt ions transport in roots and tissue tolerance to Na+ and Cl- in leaves of two contrasting mungbean genotypes, salt-tolerant Jade AU and salt-sensitive BARI Mung-6, grown in nonsaline and saline (75 mM NaCl) soil. Cryo-SEM X-ray microanalysis was used to determine concentrations of Na, Cl, K, Ca, Mg, P, and S in various cell types in roots related to the development of apoplastic barriers, and in leaves related to photosynthetic performance. Jade AU exhibited superior salt exclusion by accumulating higher [Na] in the inner cortex, endodermis, and pericycle with reduced [Na] in xylem vessels and accumulating [Cl] in cortical cell vacuoles compared to BARI Mung-6. Jade AU maintained higher [K] in root cells than BARI Mung-6. In leaves, Jade AU maintained lower [Na] and [Cl] in chloroplasts and preferentially accumulated [K] in mesophyll cells than BARI Mung-6, resulting in higher photosynthetic efficiency. Salinity tolerance in Jade AU was associated with shoot Na and Cl exclusion, effective regulation of Na and Cl accumulation in chloroplasts, and maintenance of high K in root and leaf mesophyll cells.

The unavoidable pressure injury/ulcer: a review of skin failure in critically ill patients.

Due to an ageing population and prolonged lifespan, pressure injury (PI) incidence is increasing. Patients with a PI typically endure longer hospital stays, which create a significant burden on healthcare resources and costs. With appropriate preventive interventions, most PIs can be avoided; however, skin failure may become inevitable in particular instances. These are classified as unavoidable PIs. Patients in a critical condition are exposed to a unique set of therapies, medications and bodily states. Oftentimes, these instances decrease tissue tolerance, which may promote PI formation. Patients who are critically ill, especially those with extended stays in the intensive care unit, are susceptible to skin failure due to: prolonged immobility; mechanical ventilation; acute respiratory distress syndrome; COVID-19; sepsis; multiorgan system dysfunction; vasopressor use; and treatment with extracorporeal membrane oxygenation. Poor perfusion leading to skin breakdown results from the compounding factors of circulatory collapse, build-up of metabolites, compromised lymphatic drainage, patient comorbidities, and ischaemia via capillary blockage in patients who are critically ill. In addition, similar physiology is present during end-of-life multisystem organ failure, which creates unavoidable skin deterioration. The aim of this review is to provide an overview of circumstances which decrease tissue tolerance and ultimately lead to PI development, despite adequate preventive measures in patients who are critically ill.

Mammal hibernation as a strategy for adaptation to unfavorable environmental conditions

To analyse the literature data on the survival pathways of heterothermic endotherms in unfavorable environmental conditions, during periods of low availability of food resources.The article provides data on the differences between daily and seasonal heterothermy. The features of preparation for hibernation in facultative and obligate hibernators are highlighted. Hypotheses of the origin and evolution of heterothermy are considered. The most probable causes of periodic awakenings of animals from hibernation during the hibernation period are summarised. Considerable attention is paid to the restructuring of energy metabolism during hibernation – the transition from carbohydrate to lipid metabolism. Data have been analysed indicating the importance of fatty acids obtained from food during the active summer period, both for the synthesis of reserve fats and in the regulation of hibernation. Based on data on the accumulation of monoenoic fatty acids in tissues during hibernation, it has been suggested that they have an adaptive significance aimed at limiting oxidative stress and preserving vital cell functions.The data presented can be used both for conducting fundamental research on the adaptive mechanisms of interaction of an organism with its environment, and for solving practical problems, especially when choosing models of calorie restriction or intermittent fasting, as well as studying tissue tolerance to oxidative stress and resistance to the damaging effects of ischemia – reperfusion.

Influence of test paradigm on loading dynamics during proximal femur fracture tests simulating sideways falls

Fall-related hip fractures are a serious public health issue in older adults. As most mechanistic hip fracture risk prediction models incorporate tissue tolerance, test methods that can accurately characterize the fracture force of the femur (and factors that influence it) are imperative. While bone possesses viscoelastic properties, experimental characterization of rate-dependencies has been inconsistent in the whole-femur literature. The goal of this study was to investigate the influence of experimental paradigm on loading rate and fracture force (both means and variability) during mechanical tests simulating lateral fall loadings on the proximal femur. Six pairs of matched femurs were split randomly between two test paradigms: a ‘lower rate’ materials testing system (MTS) with a constant displacement rate of 60 mm/s, and a hip impact test system (HIT) comprised of a custom-built vertical drop tower utilizing an impact velocity of 4 m/s. The loading rate was 88-fold higher for the HIT (mean (SD) = 2465.49 (807.38) kN/s) compared to the MTS (27.78 (10.03) kN/s) paradigm. However, no difference in fracture force was observed between test paradigms (mean (SD) = 4096.4 (1272.6) N for HIT, and 3641.3 (1285.8) N for MTS). Within-paradigm variability was not significantly different across paradigms for either loading rate or fracture force (coefficients of variation ranging from 0.311 to 0.361). Within each test paradigm, significant positive relationships were observed between loading rate and fracture force (HIT adjusted R2 = 0.833, p = 0.007; MTS adjusted R2 = 0.983, p < 0.0001). Overall, this study provides evidence that energy-based impact simulators can be a valid method to measure femoral bone strength in the context of fall-related hip fractures. This study motivates future research to characterize potential non-linear relationships between loading rate and fracture threshold at both macro and microscales.

Role of RIPK3 in lipid metabolism and postnatal overfeeding-induced metabolic disorders in mice

Postnatal overfeeding can increase the long-term risk of metabolic disorders, such as obesity, but the underlying mechanisms remain unclear and treatment approaches are limited. Receptor-interacting protein kinase 3 (RIPK3) is associated with several metabolic diseases. We investigated the effects of RIPK3 on neonatal overfeeding-related metabolic disorders. On postnatal day 3, litter sizes were adjusted to 9-10 (normal litters, NL) or 2-3 (small litters, SL) mice per dam to mimic postnatal overfeeding. After weaning, NL and SL mouse were fed normal diet. We generated an adeno-associated virus (AAV) carrying short hairpin RNA (shRNA) against Ripk3 and an empty vector as a control. The NL and SL groups were treated intravenously with 1×1012 vector genome of AAV vectors at week 6. The SL group showed a higher body weight than the NL group from week 3 of age through adulthood. At weeks 6 and 13, the SL group exhibited impaired glucose and insulin tolerance, RIPK3 up-regulation, and lipid accumulation in liver and adipose tissues. In the SL group, the genes involved in lipid synthesis and lipolysis were increased, whereas fatty acid β-oxidation-related genes were weakened in adipose tissue and liver. At week 13, AAV-shRNA-Ripk3 ameliorated adipose tissue hypertrophy, hepatic steatosis, insulin resistance, and dysregulated lipid metabolism in the adipose tissue and liver of SL mice. These findings support a novel mechanism underlying the pathogenesis of postnatal overfeeding-related metabolic disorders and suggest potential therapeutic targets.

XBAT31 regulates reproductive thermotolerance through controlling the accumulation of HSFB2a/B2b under heat stress conditions

Heat shock transcription factors (HSFs) play a crucial role in heat stress tolerance in vegetative tissues. However, their involvement in reproductive tissues and their post-translational modifications are not well understood. In this study, we identify the E3 ligase XB3 ORTHOLOG 1 IN ARABIDOPSIS THALIANA (XBAT31) as a key player in the ubiquitination and degradation of HSFB2a/B2b. Our results show that the xbat31 mutant exhibits a higher percentage of unfertile siliques and decreased expression of HSPs in flowers under heat stress conditions compared to the wild type. Conversely, the hsfb2a hsfb2b double mutant displays improved reproductive thermotolerance. We find that XBAT31 interacts with HSFB2a/B2b and mediates their ubiquitination. Furthermore, HSFB2a/B2b ubiquitination is reduced in the xbat31-1 mutant, resulting in higher accumulation of HSFB2a/B2b in flowers under heat stress conditions. Overexpression of HSFB2a or HSFB2b leads to an increase in unfertile siliques under heat stress conditions. Thus, our results dissect the important role of the XBAT31-HSFB2a/B2b module in conferring reproductive thermotolerance in plants.

A precise thymalfasin-regulated PRaG regimen for advanced refractory solid tumors: An open-label, prospective, multicenter clinical study (PRaG 5.0 study).

e14637 Background: PRaG regimen, which consisted of anti-PD-1 therapy, radiotherapy and GM-CSF, had a positive efficacy and tolerable safety for advanced refractory solid tumors who were heavily treated. However, severe lymphocytopenia was one of the major hurdles for immunotherapy. Thymalfasin has been wildly used as an adjuvant therapy for multiple carcinomas for elevating and sustaining the abundance of T lymphocyte. An exploratory phase II study was conducted to assess the efficacy of a meticulously thymalfasin-controlled PRaG regimen in advanced solid tumors (NCT05790447). Methods: Subjects with advanced solid tumors, having progressed beyond at least first-line chemotherapy, were eligible and treated with thymalfasin at three doses, dependent on the baseline absolute T lymphocyte count. Following seven days of thymalfasin treatment in patients with low baseline lymphocytes, they received at least two cycles of the PRaG regimen until either no suitable lesions remained for irradiation or the normal tissue tolerance dose was reached. When completing PRaG cycles, patients were maintained PD-1 inhibitor and thymalfasin until disease progression or intolerable adverse events. The primary endpoint was the overall response rate (ORR) according to RECIST 1.1. Peripheral blood samples were collected for subsequent translational research. Results: As of January 31, 2024, six patients were enrolled in the study and completed at least one tumor assessment. The ORR was 33.3%, and the disease control rate was 50.0% (2 patients with partial response (PR), one patient with stable disease (SD), and three patients with progressive disease). Four patients underwent single-cell RNA sequencing (scRNA-seq) analyses of frozen peripheral blood mononuclear cells (PBMCs) derived from before and after two cycles of therapy. Early-activated CD8+T cells, the intermediate state between the naïve-like and the effector-memory subsets, increased post-treatment, especially in three responders with PR and SD after two cycles of PRaG and thymalfasin, while a CD8+ terminally exhausted (Tex) cluster showed a decreasing trend in these responders. Seventy-six differential genes were identified in early-activated CD8+T cells, mainly enriched in activation of immune response, myeloid leukocyte activation, and T cell receptor signaling pathways (gene ontology). CCL3, PTPRC, NFKBIA, FOSB, RELB, and TGFB1 were vital genes in the gene network analysis. Conclusions: The preliminary results of the PRaG 5.0 regimen revealed a manageable safety profile and encouraging efficacy. A loading dose of thymalfasin modulation appeared to increase in early-activated CD8+T cell proportions, which might correlate with favorable responses. These results should be validated in a larger cohort of patients, and the underlying mechanisms warrant further exploration. Clinical trial information: NCT05790447 .

Monocyte/lymphocyte ratio to predict immunoradiotherapy response in patients with advanced pretreated sarcoma.

e23523 Background: Immuno-radiotherapy may improve outcomes for patients with advanced solid tumors, although optimized combination modalities remain unclear. Here, we report the sarcoma cohort analysis from the SABR-PDL1 trial that evaluated the PD-L1 inhibitor atezolizumab in combination with stereotactic body radiation therapy (SBRT) in patients with advanced cancer. Methods: Eligible patients received atezolizumab 1200 mg every 3 weeks until progression or unmanageable toxicity, together with ablative SBRT delivered concurrently with the 2nd cycle (recommended dose of 45 Gy in 3 fractions, adapted upon normal tissue tolerance constraint). SBRT was delivered to at least one tumor site, with at least one additional measurable lesion being kept from the radiation field. The primary efficacy endpoint was one-PFS rate from the start of atezolizumab. Sequential tumor biopsies were collected for deep multi-feature immune profiling and monocyte/lymphocyte ratio (sum of cells derived from the monocytic lineage including monocytes, macrophages and myeloid dendritic cells, divided by sum of lymphocytes) were computed both on tumor and blood. Results: 61 highly pretreated (median of 5 prior lines) patients with advanced sarcomas (leiomyosarcoma: 28% and other types; 32 men [53%]; median age, 47 years [range, 37-55 years]) were enrolled in two centers (France; Spain) from 03/2020 to 04/2021. All but one received atezolizumab and 56/61 (92%) received SBRT. The most frequently irradiated site was lung (n = 36/72 lesions; 50%). Treatment-related G3 (no G4-5) toxicity was observed in one (2%) patient. Median OS and PFS were respectively 12.2 [95%CI:7-18.4] and 2.5 months [95%CI:1.2-2.6], including five (8.2%) patients with PFS &gt; 1 year. Best overall responses consisted of PR (n = 3;5%) and SD (n = 36; 60%). Altogether, 182 (n = 86 paraffin; n = 96 freshly frozen) sequential tumor biopsies from 35 patients were successfully analyzed. None (0%) of the biopsies harbored tertiary-lymphoid structures. Tumor RNA sequencing analysis using independent immune deconvolution technics including CIBERSORTabs, EPIC and xCELL revealed an increased tumor infiltration of monocytic lineage-derived cells in patients who rapidly progressed. Differential gene expression analysis showed a significant upregulation of genes implicated in immunosuppression in unressponsive tumors. Unresponsive tumors were enriched with immune chemoattractants. We found higher monocyte/lymphocyte ratio in unresponsive patients compared to patients who had stable disease or tumor response both in the tumor and in the blood. Matched blood and tumor monocyte/lymphocyte ratios were significantly correlated in this population. Conclusions: This study provides new data on the feasibility, efficacy, and immune context of tumors that may help identifying patients with advanced sarcomas most likely to respond to immuno-radiotherapy. Clinical trial information: NCT02992912 .

Comparative Physiological and Transcriptomic Profiling Reveals the Characteristics of Tissue Tolerance Mechanisms in the japonica Rice Landrace Under Salt Stress

The aim of this study was to characterize the tissue tolerance mechanisms of rice under salt stress. Our preliminary experiment identified a japonica rice landrace Shuzenji-kokumai (SZK), which is considered to be tissue-tolerant because it can maintain better growth than salt-sensitive rice varieties while having a high-Na+ concentration in the shoots under salt stress. These mechanisms differ from those of most salt-tolerant rice varieties, which have low Na+ concentrations in the shoots. We compared the physiological and molecular characteristics of SZK with those of FL478, a salt-tolerant variety, and Kunishi, a salt-sensitive variety. Under salt stress conditions, SZK accumulated high levels of Na+ in the roots, leaf sheaths, and leaf blades, which were almost as high as those in the salt-sensitive Kunishi. Simultaneously, SZK maintained better growth and physiological status, as determined by its higher dry weight, lower electrolyte leakage ratio, and lower malondialdehyde concentration. Expressions of OsNHX1 and OsNHX2 were upregulated in the leaf sheaths of SZK, suggesting that Na+ might be compartmentalized in the vacuoles to avoid cytosolic Na+ toxicity. In contrast, FL478 showed upregulation of OsHKT1;5 and OsSOS1 in the roots, which may exclude Na+ from the shoots. RNA-seq analysis showed that 4623 and 1998 differentially expressed genes were detected in the leaf sheaths and leaf blades of SZK, respectively. Among them, the HSP (heat shock protein) gene expression was highly up-regulated only in SZK, indicating that SZK protects against the protein damage caused by Na+ toxicity. Our findings suggest that SZK has atypical survival mechanisms under salt stress conditions. These mechanisms offer potential traits for improving salt tolerance in rice in terms of tissue tolerance.

Stereotactic Body Radiotherapy in Recurrent and Oligometastatic Head and Neck Tumours.

The treatment of head and neck cancers (HNCs) encompasses a complex paradigm involving a combination of surgery, radiotherapy, and systemic treatment. Locoregional recurrence is a common cause of treatment failure, and few patients are suitable for salvage surgery. Reirradiation with conventional radiation techniques is challenging due to normal tissue tolerance limits and the risk of significant toxicities. Stereotactic body radiotherapy (SBRT) has emerged as a highly conformal modality that offers the potential for cure while limiting the dose to surrounding tissue. There is also growing research that shows that those with oligometastatic disease can benefit from curative intent local ablative therapies such as SBRT. This review will look at published evidence regarding the use of SBRT in locoregional recurrent and oligometastatic HNCs.

Similar and divergent responses to salinity stress of jamun (Syzygium cumini L. Skeels) genotypes.

Genetic variation for salt tolerance remains elusive in jamun (Syzygium cumini). Effects of gradually increased salinity (2.0-12.0 dS/m) were examined in 20 monoembryonic and 28 polyembryonic genotypes of jamun. Six genotypes were additionally assessed for understanding salt-induced changes in gas exchange attributes and antioxidant enzymes. Salt-induced reductions in leaf, stem, root and plant dry mass (PDM) were relatively greater in mono- than in poly-embryonic types. Reductions in PDM relative to control implied more adverse impacts of salinity on genotypes CSJ-28, CSJ-31, CSJ-43 and CSJ-47 (mono) and CSJ-1, CSJ-24, CSJ-26 and CSJ-27 (poly). Comparably, some mono- (CSJ-5, CSJ-18) and poly-embryonic (CSJ-7, CSJ-8, CSJ-14, CSJ-19) genotypes exhibited least reductions in PDM following salt treatment. Most polyembryonic genotypes showed lower reductions in root than in shoot mass, indicating that they may be more adept at absorbing water and nutrients when exposed to salt. The majority of genotypes did not exhibit leaf tip burn and marginal scorch despite significant increases in Na+ and Cl-, suggesting that tissue tolerance existed for storing excess Na+ and Cl- in vacuoles. Jamun genotypes were likely more efficient in Cl- exclusion because leaf, stem and root Cl- levels were consistently lower than those of Na+ under salt treatment. Leaf K+ was particularly little affected in genotypes with high leaf Na+. Lack of discernible differences in leaf, stem and root Ca2+ and Mg2+ contents between control and salt treatments was likely due to their preferential uptake. Correlation analysis suggested that Na+ probably had a greater inhibitory effect on biomass in both mono- and poly-embryonic types. Discriminant analysis revealed that while stem and root Cl- probably accounted for shared responses, root Na+, leaf K+ and leaf Cl- explained divergent responses to salt stress of mono- and poly-embryonic types. Genotypes CSJ-18 and CSJ-19 seemed efficient in fending off oxidative damage caused by salt because of their stronger antioxidant defences. Polyembryonic genotypes CSJ-7, CSJ-8, CSJ-14 and CSJ-19, which showed least reductions in biomass even after prolonged exposure to salinity stress, may be used as salt-tolerant rootstocks. The biochemical and molecular underpinnings of tissue tolerance to excess Na+ and Cl- as well as preferential uptake of K+, Ca2+, and Mg2+ need to be elucidated.

Abstract PO5-18-05: Assessment of the Potential of Photon mini-GRID Therapy for Pre-operative Partial Breast Cancer Treatment

Abstract Purpose We propose a new spatially fractionated radiation therapy (SFRT) technique, called mini-GRID therapy, to reduce normal tissue toxicities in pre-operative partial breast cancer radiotherapy. Mini-GRID therapy, an optimized implementation of GRID therapy, utilizes very narrow beams (widths ~ 1-2 mm) which significantly increase normal tissue tolerances. The concept, proposed by our team in 2017 [1], has been successfully implemented at Hospital de Santiago de Compostela (Spain) showing excellent results in terms of brain toxicity reduction [2]. Profiting from this remarkable increase in tolerance, this study aims to evaluate the feasibility and efficacy of photon mini-GRID therapy for pre-operative partial breast cancer treatment. Methods Ten unbiased clinical cases were selected for the study, comparing photon mini-GRID therapy with conventional broad beam radiotherapy. Monte Carlo simulations (TOPAS v.3.6) were performed based on the mini-GRID therapy implementation (megavoltage X-rays, Varian flattening-filter-free LINAC) realized at the University Hospital in Santiago de Compostela. A mean dose of 24 Gy was delivered in the PTV using three photon mini-GRID arrays with mini beams of approximately 1.8x1.8 mm² at the isocenter. The study aimed to achieve better tumor coverage than conventional pre-operative radiotherapy while ensuring comparable skin toxicity. Valley doses, determining tissue-sparing effects, were compared against organs-at-risk (OARs) tolerance limits. Results The mini-GRID therapy treatments ensured partial tumor coverage and met the dose tolerance limits for all the considered OARs, the most challenging of all being the skin [3]. Peak-to-valley dose ratio (PVDR) in the skin was higher than 3.5 for all the considered patients. Compared to standard radiotherapy (SRT) plans, mini-GRID therapy significantly reduced mean doses to the lungs, heart, and chest wall in the studied cases. Conclusion In this proof-of-concept study, we evaluated photon mini-GRID therapy with megavoltage X-rays as an alternative treatment approach for pre-operative partial breast cancer irradiation, demonstrating its feasibility and straightforward implementation. Because of its high skin and normal tissue-sparing capacities, photon mini-GRID therapy has great potential to improve pre-operative treatment outcomes. Complementary studies and clinical validation are needed to fully establish the optimal protocols and assess long-term effects, but the results encourage the integration of photon mini-GRID therapy as a promising modality for breast cancer therapy.

Differential Modulation by Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA) of Mesenteric Fat and Macrophages and T Cells in Adipose Tissue of Obese fa/fa Zucker Rats.

Polyunsaturated fatty acids (PUFAs) can alter adipose tissue function; however, the relative effects of plant and marine n3-PUFAs are less clear. Our objective was to directly compare the n3-PUFAs, plant-based α-linolenic acid (ALA) in flaxseed oil, and marine-based eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) in high-purity oils versus n6-PUFA containing linoleic acid (LA) for their effects on the adipose tissue and oral glucose tolerance of obese rats. Male fa/fa Zucker rats were assigned to faALA, faEPA, faDHA, and faLA groups and compared to baseline fa/fa rats (faBASE) and lean Zucker rats (lnLA). After 8 weeks, faEPA and faDHA had 11-14% lower body weight than faLA. The oral glucose tolerance and total body fat were unchanged, but faEPA had less mesenteric fat. faEPA and faDHA had fewer large adipocytes compared to faLA and faALA. EPA reduced macrophages in the adipose tissue of fa/fa rats compared to ALA and DHA, while faLA had the greatest macrophage infiltration. DHA decreased (~10-fold) T-cell infiltration compared to faBASE and faEPA, whereas faALA and faLA had an ~40% increase. The n3-PUFA diets attenuated tumour necrosis factor-α in adipose tissue compared to faBASE, while it was increased by LA in both genotypes. In conclusion, EPA and DHA target different aspects of inflammation in adipose tissue.