Tissue Tolerance Research Articles

Seed priming with NaCl helps to improve tissue tolerance, potassium retention ability of plants, and protects the photosynthetic ability in two different legumes, chickpea and lentil, under salt stress

Seed priming with NaCl mimicked the conditions of natural priming to improve the tissue tolerance nature of sensitive legumes, which helps to maintain survivability and yield in mildly saline areas. Seed priming with NaCl is a seed invigoration technique that helps to improve plant growth by altering Na+ and K+ content under salt stress. Legumes are overall sensitive to salt and salinity hampers their growth and yield. Therefore, a priming (50mM NaCl) experiment was performed with two different legume members [Cicer arietinum cv. Anuradha and Lens culinaris cv. Ranjan] and different morpho-physiological, biochemical responses at 50mM, 100mM, and 150mM NaCl and molecular responses at 150mM NaCl were studied in hydroponically grown nonprimed and primed members. Similarly, a pot experiment was performed at 80mM Na+, to check the yield. Tissue Na+ and K+ content suggested NaCl-priming did not significantly alter the accumulation of Na+ among nonprimed and primed members but retained more K+ in cells, thus maintaining a lower cellular Na+/K+ ratio. Low osmolyte content (e.g., proline) in primed members suggested priming could minimize their overall osmolytic requirement. Altogether, these implied tissue tolerance (TT) nature might have improved in case of NaCl-priming as was also reflected by a better TT score (LC50 value). An improved TT nature enabled the primed plants to maintain a significantly higher photosynthetic rate through better stomatal conductance. Along with this, a higher level of chlorophyll content and competent functioning of the photosynthetic subunits improved photosynthetic performance that ensured yield under stress. Overall, this study explores the potential of NaCl-priming and creates possibilities for considerably sensitive members; those in their nonprimed forms have no prospect in mildly saline agriculture.

CAR Tregs protect alloimmune islets against autoimmune destruction

Abstract Regulatory T cell (Treg) therapy is a promising approach to induce tolerance of transplanted tissues and/or self antigens that drive autoimmunity. Early clinical trials with polyclonal Tregs have proven feasible, safe and tolerable. The next wave of Treg therapies is genetically enhanced with antigen specificity. We have previously shown that Tregs engineered to express a chimeric antigen receptor specific for HLA-A2 (A2-CAR) delay rejection of HLA-A2+ grafts; however, it was unknown whether they would limit T cell responses targeting antigens other than HLA-A2 via bystander suppression. To investigate this possibility, we used a model of HLA-A2-mismatched islet transplantation and asked if A2-CAR Tregs could inhibit rejection mediated by diabetogenic T cells. HLA-A2+ islets (150–200) isolated from NOD-HLA-A2+ mice were transplanted into immunodeficient NSG mice. After 3.5 weeks, diabetogenic BDC2.5 CD4+ T cells were adoptively transferred with or without polyclonal or A2-CAR Tregs (1 CD4+:5 Tregs). Mice that received BDC2.5 CD4+ T cells without Tregs or polyclonal Tregs rapidly developed hyperglycemia. In contrast, mice that received A2-CAR Tregs were completely protected from hyperglycemia. Longitudinal monitoring of injected Tregs showed that A2-CAR Tregs were more numerous and activated relative to polyclonal Tregs. Removal of the HLA-A2+ islet graft from a protected A2-CAR Treg-treated mouse did not induce hyperglycemia, suggesting that the ability of BDC2.5 CD4+ T cells to mediate autoimmune attack of the endogenous (HLA-A2-) pancreas was suppressed. These data suggest that A2-CAR Tregs mediate bystander suppression in vivo and may have the ability to induce long-term tolerance to both allo- and autoantigens. Supported by a CIHR Canada Graduate Scholarship doctoral research award and a CIHR foundation grant (FDN-154304).

Regulatory T cells in peripheral tissue tolerance and diseases.

Maintenance of peripheral tolerance by CD4+Foxp3+ regulatory T cells (Tregs) is essential for regulating autoreactive T cells. The loss of function of Foxp3 leads to autoimmune disease in both animals and humans. An example is the rare, X-linked recessive disorder known as IPEX (Immune Dysregulation, Polyendocrinopathy, Enteropathy X-linked) syndrome. In more common human autoimmune diseases, defects in Treg function are accompanied with aberrant effector cytokines such as IFNγ. It has recently become appreciated that Tregs plays an important role in not only maintaining immune homeostasis but also in establishing the tissue microenvironment and homeostasis of non-lymphoid tissues. Tissue resident Tregs show profiles that are unique to their local environments which are composed of both immune and non-immune cells. Core tissue-residence gene signatures are shared across different tissue Tregs and are crucial to homeostatic regulation and maintaining the tissue Treg pool in a steady state. Through interaction with immunocytes and non-immunocytes, tissue Tregs exert a suppressive function via conventional ways involving contact dependent and independent processes. In addition, tissue resident Tregs communicate with other tissue resident cells which allows Tregs to adopt to their local microenvironment. These bidirectional interactions are dependent on the specific tissue environment. Here, we summarize the recent advancements of tissue Treg studies in both human and mice, and discuss the molecular mechanisms that maintain tissue homeostasis and prevent pathogenesis.

Superior salt tolerance in wild soybean (G. soja) is associated with better ion ‘exclusion’ ability from leaves and mesophyll cells than cultivated soybean genotypes (G. max)

Soybean (Glycine max) is a salt-sensitive crop. However, wild soybean (Glycine soja) is a potential source of germplasm to improve salt tolerance in G. max. This study evaluated the response of cultivated soybean (G. max cv. Bunya and Lee) and wild soybean (G. soja) to ionic components of salt stress to test the hypothesis that wild and cultivated soybean genotypes differ in leaf tissue tolerance to Na+ and/or Cl–. The soybean genotypes were subjected to NaCl, Na+ salts, and Cl– salts at 50, 75 and 100 mM, and a non-saline control to analyse the effect of salts/ions on growth, tissue ion concentrations and photosynthesis. Cryo-SEM X-ray microanalysis was used to evaluate cellular [Na], [Cl] and [K] in various cell types within leaflets. NaCl and Na+ salts reduced shoot and root dry mass more than Cl– salts in the three genotypes. Soja maintained higher photosynthetic rates (84 % of control) than Lee (70 % of control) and Bunya (60 % of control) in the 75 mM treatments. Soja had lower [Na+] in leaves and mesophyll cells than Lee and Bunya. G. soja had greater tolerance to salinity than G. max due to better ‘ion exclusion’ from leaves and photosynthetically active mesophyll cells.

PSTPIP2 alleviates obesity associated adipose tissue inflammation and insulin resistance in diabetes mice through promoting M2 macrophage polarization via activation of PPARγ

BackgroundProline-serine-threonine phosphatase-interacting protein 2 (PSTPIP2) plays a role in inflammatory disease. In diabetes, very little is known about PSTPIP2 until now. Hence, this study aimed to determine PSTPIP2 functional role in diabetes. MethodsDiabetes mouse model was constructed by feeding high fat diet (HFD). Intraperitoneal glucose tolerance test and intraperitoneal insulin tolerance test were examined the glucose and insulin tolerance. The expression of genes and proteins was detected by quantitative real time PCR, immunohistochemistry and western blotting. The pathological changes of epididymal adipose tissues were examined by hematoxylin-eosin staining. RAW264.7 macrophages were treated with GW9662 (PPARγ antagonist). Flow cytometry examined the proportion of M1/M2 macrophages. ResultsHFD enhanced the body weight, glucose and insulin tolerance, and inhibited PSTPIP2 expression in mice. PSTPIP2 overexpression alleviated glucose and insulin tolerance, reduced inflammation and macrophage accumulation in the epididymal adipose tissues of diabetic mice. The expression of iNOS and TNF-α was increased, the expression of IL-10 and Arg-1 was decreased in diabetic mice, which was abrogated by PSTPIP2 overexpression. In vitro, PSTPIP2 overexpression reduced the proportions of iNOS-positive cells and enhanced the proportions of CD206-positive cells in RAW264.7 cells. PPARγ and p-STAT6 were up-regulated, STAT6 was down-regulated in RAW264.7 cells. GW9662 impaired PSTPIP2 overexpression-mediated up-regulation of Arg-1, YM-1 and FIZZ1 in RAW264.7 cells. ConclusionPSTPIP2 alleviates obesity associated adipose tissue inflammation and insulin resistance in diabetic mice through promoting M2 macrophage polarization via activation of PPARγ, suggesting that PSTPIP2 is a prospective target for diabetes treatment.

The Technique Triad Theory

A common theme that has been recently perpetuated through the medical community is the oversimplification of injury science to the equation of load versus capacity and the disregard for the influence of movement quality. The Adaptation Model is based on the belief that one can recover and/or adapt to any stimulus or stress that is gradually applied as long as it does not breach the system’s capacity; and that, as humans, we can infinitely become better suited to our environment regardless of what this environment may entail. Many who support this hypothesis reject the importance of biomechanics, technique, and movement proficiency in regard to injury prevention and rather promote this idea of adaptation in isolation. Building capacity through many repetitions gradually involves neurophysiological adaptations that improve skill acquisition, neuromuscular efficiency, and technique. Therefore the “adaptation model” inherently involves an element of “technique” in itself. “Load” and “Capacity” play a key role in one’s ability to adapt, grow and perform at their best. However, this duality is incomplete without the 3rd pillar - technique. In order to maintain ideal movement proficiency and drive physiological adaptations, we must increase the load within the context of what our skill and technique will allow. Although technique quality is described often on a sliding spectrum-like scale, as requiring sufficient competency within certain fundamentals as a prerequisite to increasing load allows you to improve skill without increasing the risk of breaching your tissue tolerances. Increase load too quickly, and you risk sporadic and uncontrolled migration of forces onto parts of your body or tissue systems that do not yet have the required capacity to handle such stress. With the proper movement patterns ingrained and the appropriate dosage or load progressively challenging the capacity, the programming now reflects the intensity of such stimuli based on the athlete’s ability to recover from the fatigue debt created in training. As the programming progresses and the load is increased, capacity requires technique and the ability to move proficiently through the sport-specific movement. 1) Technique permits load because load requires technique, 2) Load challenges capacity because capacity dictates load and 3) Capacity requires technique because technique protects and maximizes capacity.

Effect of ischemic preconditioning on skeletal tissue tolerance after warm venous ischemia

Free muscular flaps are commonly used in plastic surgery. The main reason of failure is thrombosis induced by a phenomenon called ischemia reperfusion. Preconditioning showed an interest to prevent ischemia reperfusion injury in transplantation surgery. The aim of the study is to evaluate the effect of ischemic preconditioning on skeletal tissue tolerance after warm venous ischemia. We realized an experimental study with latissimus dorsi flaps of 12 pigs, divided in 6 groups in function of their time of preconditioning and duration of warm venous ischemia. A morphologic analysis was performed measuring cell's diameter and interstitial tissue area and notifying the presence or absence of neutrophils, necrosis or intravascular thrombosis. To detect inflammation, necrosis or hypoxia, immunohistochemistry was effectuated using the follow primary antibodies, AIF, HIF1 alpha, caspase 3, SOD 1 and PKC epsilon. TUNEL assay showed apoptosis cells, were realized. One way Anova test was performed to compare the quantitative evolution over time of histological parameters and rate of apoptosis. Preconditioning of 40min or 1hour allowed to reduced ischemia reperfusion lesions: no cellular or interstitial oedema, reduction of neutrophils infiltrate and intravascular thrombus. TUNEL assay showed a higher rate of apoptosis nucleus for the control group E compared to preconditioning group C and D. Immunohistochemistry results were no relevant. We showed a diminution of lesions of ischemia reperfusion for experimental groups with preconditioning: diminution of interstitial oedema, of cellular oedema, diminution of neutrophils infiltrated and level of apoptosis cells. Preconditioning of 40minutes were as efficient as one hour.

Drug‐Free Biomimetic Oxygen Supply Nanovehicle Promotes Ischemia‐Reperfusion Therapy in Stroke

AbstractRecanalization intervention is the primary recommended therapy for ischemic stroke, but the rapid progression of brain damage results in a very narrow time window for ischemia‐reperfusion therapy, which remains the biggest obstacle for ischemic stroke treatment. Herein, a drug‐free biomimetic nanovehicle capable of improving cerebral ischemic tolerance and thus promoting ischemia‐reperfusion therapy is reported. The nanovehicle comprises an amphiphilic polyfluorocarbon, which delivers oxygen to alleviate the hostile hypoxic environment of ischemic brain, and Pluronic P123, which inhibits matrix metalloproteinase‐9 to protect the blood–brain barrier (BBB). When intravenously injected into ischemic stroke rats with transient middle cerebral artery occlusion, these nanovehicles are able to preferentially access cerebral ischemic lesions in an inflammation‐directed manner, conferring robust ischemic tolerance and reperfusion resistance of brain tissues for ischemia‐reperfusion therapy. Furthermore, it is also demonstrated that the nanovehicle is beneficial for mice with permanent ischemic stroke induced by photothrombosis. This work suggests a promising strategy with hypoxia relief and BBB protection for ischemic stroke therapy.

Worsened Stroke Outcome in a Model of Preeclampsia is Associated With Poor Collateral Flow and Oxidative Stress.

Preeclampsia increases the incidence of maternal stroke, a devastating condition that is on the rise. We investigated stroke outcome in a model of experimental preeclampsia with and without treatment with clinically relevant doses of magnesium sulfate (experimental preeclampsia+MgSO4) compared to normal late-pregnant and nonpregnant rats. Transient middle cerebral artery occlusion was used to induce focal stroke for either 1.5 or 3 hours. Infarct volume and hemorrhagic transformation were determined as measures of stroke outcome. Changes in core middle cerebral artery and collateral flow were measured by dual laser Doppler. The relationship between middle cerebral artery perfusion deficit and infarction was used as a measure of ischemic tolerance. Oxidative stress and endothelial dysfunction were measured by 3-nitrotyrosine and 8-isoprostane, in brain and serum, respectively. Late-pregnant animals had robust collateral flow and greater ischemic tolerance of brain tissue, whereas experimental preeclampsia had greater infarction that was related to poor collateral flow, endothelial dysfunction, and oxidative stress. Importantly, pregnancy appeared preventative of hemorrhagic transformation as it occurred only in nonpregnant animals. MgSO4 did not provide benefit to experimental preeclampsia animals for infarction. Stroke outcome was worse in a model of preeclampsia. As preeclampsia increases the risk of future stroke and cardiovascular disease, it is worth understanding the influence of preeclampsia on the material brain and factors that might potentiate injury both during the index pregnancy and years postpartum.

Association of Serum Omentin-1 Concentration with the Content of Adipose Tissue and Glucose Tolerance in Subjects with Central Obesity

Omentin is one of the few adipokines with potentially beneficial metabolic effects. The main aim of this study was to determine the association between serum omentin-1 levels and the occurrence of central obesity and abnormal glucose tolerance, taking into account gender. The study involved 88 participants aged 30-60, including 47 women and 41 men. Two subgroups among the obese subjects were distinguished-those with normal and abnormal glucose tolerance. Anthropometric and biochemical examinations and blood pressure measurements were performed. Omentin-1 concentrations were significantly lower among patients with obesity compared to those without obesity (p = 0.027) and, similarly, comparing men with abnormal glucose tolerance with men with normal glucose tolerance (p = 0.035). In contrast, no such pattern was observed in women. The multivariable regression model showed a significant effect of gender status and important factors of tissue insulin sensitivity, such as OGGT results, WHR and amount of body fat, on the variability of serum omentin-1 concentration in the entire study population (R2adj. = 13.7%; p = 0.003). High omentin-1 levels found in men with obesity and normal glucose tolerance suggest that omentin-1 protects against metabolic disorders associated with obesity in the male population.

Salinity responses in 24 guar genotypes are linked to multigenic regulation explaining the complexity of tolerance mechanisms in planta

AbstractGuar (Cyamopsis tetragonoloba (L.) Taub.) is an economically important, drought‐tolerant legume crop affected by moderate to high salinity. Guar has various industrial applications, including gum extracted from seeds that is widely used in the oil and natural gas industries. In this investigation, we evaluated the salinity tolerance of different guar genotypes and their relation to genetic mechanisms regulating guar responses to salinity stress. We screened 24 guar genotypes in a greenhouse lysimeter system under control (electrical conductivity (EC) = 1.46 dS m−1) and high salinity (EC = 13.65 dS m−1) treatments. Both length and biomass of shoots were significantly affected by salinity compared to roots, indicating higher shoot than root sensitivity to salinity. Twenty‐four genotypes were classified based on salt tolerance index for each trait. Tissue ion analysis revealed that roots accumulated over 10‐fold higher Na than leaves, demonstrating that guar effectively regulated the root‐to‐shoot movement of Na+. However, higher Cl concentrations in leaves than roots indicated less regulatory control of Cl− movement. Based on the morphological traits and tissue ion analysis, six genotypes (PI 164486, PI 253186, PI 26152, PI 158125, PI 179926, and PI 263698) with different responses to salinity were selected for gene expression analysis. Expression patterns of different genes showed that a complex network of component traits, including Na+ exclusion, Cl− exclusion, and tissue tolerance, regulate salinity tolerance in guar. Hence, the genetic information about different component traits will benefit guar breeders in developing new varieties that are more tolerant to salinity than current ones.

Optimal plan target in cases with locally advanced nasopharyngeal cancer: Comparison of VMAT, IMRT, hybrid, and tomotherapy results.

In locally advanced nasopharyngeal cancer (NC), the spread of the disease, proximity to critical structures, and high dose requirement for tumor control may complicate the treatment plan. In this study, VMAT/IMRT/hybrid/tomotherapy plans were made to reach the safest and most effective dose distribution for each of the patients and the results were compared. Double volumetric-modulated arc therapy (VMAT) and 7- and 9-field intensity-modulated radiation therapy (IMRT) plans were made to 21 locally advanced NCs with Varian Trilogy System. It was observed that appropriate dose distributions could not be achieved with IMRT or VMAT, and hybrid IMRT-VMAT plans were made. All cases were also planned with Tomotherapy Precision System, and the data of four different techniques were compared retrospectively. For normal tissue tolerances in 73 structures could not be obtained with VMAT and 38 structures with IMRT whereas the desired tolerance was provided with the hybrid plan. Hybrid plans were made with an average of 14 VMATs and 20 IMRTs. The maximum brainstem and spinal cord doses were found significantly lower in hybrid and tomotherapy techniques. Homogeneity index (HI) and conformity index (CI) values were the best in hybrid plans. No statistically significant difference between the hybrid plan and tomotherapy in terms of normal tissue tolerance doses and HI whereas a significant difference was found in the hybrid plan for CI. It was observed that the most ideal plans for the locally advanced NC could be obtained with tomotherapy and hybrid plan techniques that the better protection in critical structures and desired dose distribution at target volumes.

Beyond traditional light: NIR-II light-activated photosensitizers for cancer therapy.

With increasing demand for the accurate and safe treatment of cancer, non-invasive photodynamic therapy (PDT) has received widespread attention. However, most conventional photosensitizers are typically excited by short-wavelength visible light (400-700 nm), thus substantially hindering the penetration of light and the therapeutic effectiveness of the PDT procedure. Fortunately, near-infrared (NIR) light (>700 nm), in particular, light in the second near-infrared region (NIR-II, 1000-1700 nm) has a higher upper radiation limit, greater tissue tolerance, and deeper tissue penetration compared with traditional short-wavelength light excitation, and shows considerable potential in the clinical treatment of cancer. Therefore, it is of paramount importance and clinical value to develop photosensitizers that are excited by NIR-II light. In this review, for the first time we focus completely on recent progress made with various NIR-II photosensitizers for cancer treatment via PDT, and we briefly present the ongoing challenges and prospects of currently developed NIR-II photosensitizers for clinical practice in the near future. We believe that the above topics will inspire broad interest in researchers from interdisciplinary fields that include chemistry, materials science, pharmaceuticals, and clinical medicine, and provide insightful perspectives for exploiting new NIR-II photosensitizers for biomedical applications.

Protective Effect of Curcumin on CA1 Region of Hippocampus in Rat Model of Ischemia/ Reperfusion Injury:.

The brain is the most complex and vital organ of the human body. It requires 20-25 % of the total oxygen supply. Because of the limited oxygen and glucose reserves, brain tissue is sensitive to ischemic injury. Indeed, the tolerance of brain tissue for ischemic injury is fragile. Currently, few therapeutic strategies could provide complete neuroprotection. Despite decades of intense research, the beneficial treatment of stroke remains limited. Hence, we aimed to investigate the effect of curcumin on the CA1 region of the hippocampus in a rat model of ischemia/reperfusion (I/R) injury. In this experimental research, 24 male Wistar rats were randomly divided into three groups (n=8 per group) as control, I/R, and I/R plus curcumin. All rats underwent bilateral common carotid artery ligation followed by reperfusion. In the treatment group, curcumin (300 mg/kg) was injected 30 minutes before ischemia. Morphological changes of the hippocampus were assessed using Nissl staining, and apoptosis was determined via TUNEL immunohistochemical assays. Nissl staining data showed that the administration of curcumin significantly ameliorated the CA1 pyramidal cell loss due to transient global I/R injury. TUNEL immunohistochemical assays demonstrated that the number of apoptotic cells was significantly lower in the curcumin group than in the I/R groups. Our study demonstrates that curcumin had beneficial activity against ischemia and played a neuroprotective role in the pathogenesis of I/R injury.

5-Heptadecylresorcinol Regulates the Metabolism of Thermogenic Fat and Improves the Thermogenic Capacity of Aging Mice via a Sirtuin 3–Adenosine Monophosphate-Activated Protein Kinase Pathway

5-Heptadecylresorcinol (AR-C17), a well-known biomarker for whole grain rye consumption, is a primary homolog of alkylresorcinols. In this study, the effects of AR-C17 on the thermogenesis of brown adipocytes and 3T3-L1 adipocytes were investigated. The results showed that AR-C17 increased sirtuin 3 (Sirt3) expression, and the expressions of specific thermogenic genes in adipocytes were increased. Furthermore, AR-C17 increased the mitochondrial functions during the thermogenic activation of adipocytes. In in vivo study, AR-C17 increased the cold tolerance and thermogenic capacity of adipose tissues in aging mice. In addition, Sirt3 activity was required for AR-C17-induced thermogenesis. Meanwhile, AR-C17 increased adenosine monophosphate-activated protein kinase (AMPK) phosphorylation, and AMPK was involved in the regulation of AR-C17 on thermogenic adipocytes. Mechanically, AR-C17 upregulated a Sirt3-AMPK positive-feedback loop in adipocytes and further increased the expression of uncoupling protein 1 to activate thermogenesis. This study indicated that AR-C17 could be a promising thermogenic activator of adipocytes to alleviate obesity and aging-associated metabolic diseases.

Vasopressors and Pressure Injury Risk in the Critically Ill

We have not done any further analysis; therefore, we still do not know the exact etiological factor (vasopressor vs shock sequelae vs overall severity of illness) that places the patient at increased risk for PI. We strongly suspect that vasopressors and especially vasopressin play a significant role in PI development. Although we know that cutaneous manifestations associated with vasopressor medications exist, the evidence is not strong as to whether the associated gangrene is related to vasopressors or to the sequelae of shock that the vasopressors were administered to treat.When patients are receiving vasopressors, PI interventions such as more frequent repositioning or small repositioning shifts may be indicated, depending on the support surface in use and the patient’s individual tissue tolerance. For example, in patients with anasarca, tissue tolerance is severely compromised and increased frequency of repositioning/off-loading may be necessary. The use of prophylactic multilayer silicone foam dressings, if they are not already in use, should be considered as well.Interestingly, in the International Pressure Injury Guidelines published in 2019, skin temperature is mentioned as a potential PI risk factor because it can affect tissue tolerance to mechanical loads. In addition, patients who are diaphoretic may be more susceptible to pressure.Lateral rotation should not be used for repositioning patients because the lateral movement can actually increase shear and thus increase PI risk. Foam wedges are effective if you can use them to off-load pressure adequately. Pillows can be effective, as well, as long as these devices are used to prop the patient in a 30° side-lying position.

Difficulties and prospects of rational therapy of ischemic strokes

Despite significant progress in medical technology, many topical issues in neurology remain unresolved; among the latter, acute cerebrovascular accidents (strokes) continue to be one of the most important medical and social problems of the modern world, since their rates of morbidity, mortality and disability are steadily growing. The increase in the incidence of strokes over the past 30 years by 70% reflects the imperfection of modern medical strategies for the primary prevention of stroke and measures for their implementation among the population, which dictates the need to revise the prevailing ideas about the etiology, pathogenetic mechanisms and therapeutic approaches to managing patients with cerebrovascular pathology. The article presents a classification of strokes, a critical analysis of vascular risk factors (in particular, the emergence of new ones, such as acute coronavirus infection COVID-19), fundamental elements of the ischemic cascade, pathomorphological and pathophysiological consequences of ischemic damage to the central nervous system (necrosis and apoptosis of neurons, diaschisis in the penumbra zone), current theoretical (targets of drug exposure) and practical (therapeutic window) aspects of therapy and prevention of acute cerebrovascular accidents are outlined. The place and importance of the use of neuroprotective drugs in the combined therapy of patients with acute and chronic cerebrovascular pathology has been demonstrated. Particular attention is focused on neurometabolic drugs with a multimodal mechanism of action, which not only protect the neuronal cytoskeleton, but also increase the tolerance of brain tissue to hypoxia.

A randomised phase II trial of radiotherapy dose escalation, facilitated by intensity-modulated arc therapy techniques, in high-risk neuroblastoma

<h3>Objectives</h3> This trial compared intensity modulated arc therapy (IMAT) with conventional techniques for high-risk neuroblastoma, to establish whether IMAT could enable a higher radiation dose than standard to be given without exceeding normal tissue dose objectives. The aim was to determine the radiotherapy dose for use in a subsequent international randomised phase III trial. <h3>Methods</h3> Patients were randomised to receive either 21 Gy in 14 fractions, or 36 Gy in 24 fractions. The tumour volume and organs at risk were delineated according to a standard protocol. All patients were dual planned with both conventional and IMAT techniques. A quality assurance team prospectively reviewed the contours and the plans. The better technique, based on planning target volume dose achieved and organ at risk sparing, was selected for use. <h3>Results</h3> From 2017 to 2020, fifty patients were recruited and randomised, 25 to each arm. All 50 patients underwent radiotherapy planning, but only 43 completed protocol treatment, all with the IMAT technique. The IMAT technique improved planning target volume conformity and heterogeneity indices significantly. In the 21 Gy arm, the dose delivered in all patients was 21 Gy. In the 36 Gy arm, the median dose delivered was 36 Gy (range 21 Gy to 36 Gy). Disease progression occurred in 18 patients and 16 patients have died. At two years, the overall survival was 70%, and the event free survival was 60%. This phase II trial was not powered to detect a difference between the arms, and no difference in event-free or overall survival was observed. <h3>Conclusion</h3> This trial confirms that delivery of 36 Gy is possible using an IMAT technique without exceeding normal tissue tolerance. The new SIOPEN High-Risk 2 trial contains a Phase III randomisation comparing 36 Gy with 21.6 Gy inpatients with residual disease after surgery.

Relative contribution of ion exclusion and tissue tolerance traits govern the differential response of rice towards salt stress at seedling and reproductive stages

Rice shows considerable variability toward salinity stress at the seedling and reproductive stages. Though ion exclusion (IE) is one of the most important tolerance strategies, some good ion-excluders do not necessarily show an expected level of tolerance at the reproductive stage. Here, we aimed to identify what could be the additional factors that help a few genotypes to tolerate salt stress at the reproductive stage more efficiently than others. We took rice genotypes having stage-specific variations in salt-tolerance ability and studied their physiological and molecular responses towards salt stress at both seedling and reproductive stages. We also studied the contribution of the tissue tolerance (TT) trait to understand its stage-specific influence on salinity tolerance. Tissue Na+ and K+ concentrations, and the values of selective transport of K+ over Na+ suggested that FL478 and AC41585 were very good ion excluders, while Rashpanjor and IR29 were moderate and poor ion excluders, respectively. The gene expression profiles of different Na+/H+ transporters; high-affinity K+ transporters, K+ uptake channels/pumps, and H+-pumps indicate very high IE behavior of FL478 and AC41585, which perfectly resembles the phenotypic manifestation of salt tolerance at the seedling stage. But, even with such dominating IE, FL478 failed to show a similar level of tolerance, while AC41585 could. Interestingly, we observed a significant difference in TT (measured in terms of LC50 score) of these genotypes. IR29 showed the highest TT, followed by Rashpanjor and AC41585, while it was the least in FL478. We conclude that only IE, without much contribution of TT, could be enough for seedling stage tolerance, however, may not be sufficient for the reproductive stage tolerance. Rather a fine balance between IE and TT is crucial for prolonged salt tolerance at the reproductive stage.

О ЦЕЛЕСООБРАЗНОСТИ ПРОВЕДЕНИЯ ПОВТОРНОЙ РАДИОТЕРАПИИ ПРИ РЕЦИДИВАХ И ПРОДОЛЖЕННОМ РОСТЕ РАНЕЕ ОБЛУЧЕННЫХ ОПУХОЛЕЙ РАЗЛИЧНОЙ ЛОКАЛИЗАЦИИ

Introduction: The development of a recurrence or a second tumor in previously irradiated patients requires, in some cases, repeated radiotherapy (reirradiation) of the previously irradiated tissue volume. In the past decades, it was widely believed that it was possible to irradiate one anatomical zone in curative doses only once (taking into account the tolerance of healthy tissues) and the issue of repeated irradiation was practically not discussed (there are only a few studies). This approach was due to the fact that the use of old technologies did not allow sufficient protection of healthy tissues surrounding the tumor, which led to severe complications. Due to the development of radiotherapy technologies and new advances in radiobiology, the number of studies on the re-irradiation of recurrent tumors has recently increased significantly, however, they are mainly retrospective in nature and do not have a sufficient evidence compared to indications for primary radiotherapy. However, reirradiation can be used not only for palliative purposes, but also to achieve long-term local control. Modern medical approaches and technical capabilities make it possible to re-irradiate tumors of any localization, up to the second curative dose. Purpose: To investigate the expediency of repeated irradiation of patients with different tumor localizations, taking into account the survival rates of patients, possible complications and subsequent quality of life. Materials and methods: For the first time in Armenia, an analysis of the results of reirradiation is carried out on the basis of the experience of one clinic. The results of treatment of 1300 patients, who received radiotherapy at the IRA MEDICAL Group Radiotherapy Center from March 2019 to March 2022 were studied. The study included 52 patients, who received the second course of RT, which accounted for 4% of the total number of patients. The median age of patients was 60.5 years (22 - 81), including 22 men, 30 women, based on pathologies: CNS tumors - 17 patients, brain metastasis - 10, gynecology - 6, head and neck tumors - 6, metastatic skeletal bone lesions - 4, breast cancer - 3, other localizations - 6. Stage of the disease: III - 7 patients, IV - 37, unclassified - 8. The mean interval between two courses of radiotherapy was 34.5 months (1.5 - 252). The median total equivalent dose from two irradiation courses is 99 Gy (56-121). Except of the patients, who received reirradiation for metastatic relapse, the total equivalent dose was 102 Gy (84–121), and the median follow-up time after reirradiation was 9 months (4–29.5). Results: The average life expectancy of patients, who died during the observation period was 6.5 months (1-23). In 7 out of 52 patients, who initially had low KPS (60%), survival was up to 3.5 months or less. After excluding these patients from further statistical analysis, the median survival of the remaining patients was 10 months (4 – 23). As of March 31, 2022, 31 patients (59.6%) are alive, with an average follow-up of 13 months (5 – 29.5). The number of post-radiation complications and the quality of life of patients were also assessed. There were no treatment related deaths or reduced quality of life in the early stages. The results of this prospective study demonstrate that the use of the latest technologies in repeat radiotherapy can improve survival and quality of life in these patients. Thanks to new technologies, it is possible to conduct a repeated course of radiotherapy even in curative doses. When planning the second therapeutic or palliative course of radiotherapy, it is necessary to carefully select patients, taking into account a number of factors related to the previous treatment and the individual characteristics of the patient. After completion of the study, we plan to create recommendations on the criteria for selecting candidates for re-irradiation.