Tissue Protection Research Articles

S-10-6: BLOOD PRESSURE TARGETS FOR SECONDARY PREVENTION OF STROKE

The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) showed the benefits of blood pressure (BP) lowering for secondary stroke prevention in stroke survivors for the first time after a long dispute in the last century and triggered active hypertensive therapy for stroke patients globally in this century. A post hoc analysis of PROGRESS demonstrated that both the lowest risks of ischemic stroke and of hemorrhagic stroke were among the one-quarter of patients with the lowest achieved follow-up BP levels (median 112/72 mmHg), and that these risks increased progressively with higher follow-up BP levels in the large cohort of patients with previous stroke or transient ischemic attack. A similar tendency for an increased risk of ischemic/hemorrhagic stroke by higher follow-up BP levels was reproduced in subsequent stroke trials. Several trials sought to clarify the preventive effect against recurrent stroke by randomizing patients into two groups with different BP lowering targets. In patients with recent lacunar stroke in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial, lowering systolic BP to < 130 mmHg significantly reduced the risk of intracerebral hemorrhage (ICH) by 63% and insignificantly reduced the risk of ischemic stroke by 16% compared to lowering to 130–149 mmHg. The Recurrent Stroke Prevention Clinical Outcome (RESPECT) Study, involving patients having a history of stroke within the previous 3 years showed similar results: lowering BP to < 120/80 mmHg, relative to < 140/90 mmHg, reduced the risk of ICH by 91% and that of ischemic stroke by only 9%. These trials failed to demonstrate a significant reduction in the risk of any stroke as the primary outcome by intensive BP lowering, since the incidence of ischemic stroke was much higher than that of ICH for both trials. A meta-analysis of these two trials and two more small studies finally succeeded in showing a statistically significant 22% reduced risk for any stroke recurrence by lowering systolic BP to at least < 130 mmHg. The current guidelines recommend systolic BP control aiming at < 130 mmHg or 120–130 mmHg for adults who experience ischemic stroke. RESPECT is epochal as the first large population trial to examine the importance of systolic BP lowering to < 120 mmHg. Such strict control would undoubtedly decrease incidental ICH, especially for patients taking antithrombotic agents. However, the necessity of strict BP control for protection of brain tissues from ischemic injury is still an unresolved matter that needs to be addressed in future studies.

Drill Bone with Both Hands: Plunge Depth and Accuracy with 4 Bracing Positions.

A prospective study with randomized crossover was conducted to assess the effect of 4 bracing positions on orthopaedic surgical trainee performance in a simulated bone drilling task. Linear mixed effects models considering participant training level, preferred bracing position, height, weight, and drill hole number were used to estimate pairwise and overall comparisons of the effect of each bracing position on 2 primary outcomes of drilling depth and accuracy. A total of 42 trainees were screened and 19 were randomized and completed the study. Drill plunge depth with a 1-handed drilling position was significantly greater by pairwise comparison to any of the 3 double handed positions tested: a soft tissue protection sleeve in the other hand (0.41 mm, 95% confidence interval [CI] 0.80-0.03, p = 0.031), a 2-handed position with the contralateral small finger on bone and the thumb on the drill (0.42 mm, 95% CI 0.06-0.79, p = 0.018), and a 2-handed position with the contralateral elbow braced against the table (0.40 mm, 95% CI 0.02-0.78, p = 0.038). No position afforded a significant accuracy advantage (p = 0.227). Interactions of participant height with plunge depth and accuracy as well between drill hole number and plunge depth were observed. Orthopaedic surgical educators should discourage trainees from operating a bone drill using only 1 hand to reduce the risk of iatrogenic injury due to drill plunging. Therapeutic Level II.

A method for adjusting MLC leaf positions outside a reference region for VMAT plans in a commercial treatment planning system.

Multileaf collimators (MLC) leaf positions in a volumetric modulated arc therapy (VMAT) plan is determined from inverse treatment planning process. On the isocenter plane, leaf projections should not be set too far out of projected PTV boundary. In this study we developed an automatic method of adjusting leaf positions outside a reference region of interest (ROI) for VMAT plans generated in Pinnacle treatment planning system (TPS). The proposed method consisted of a Pinnacle script and a Python program. It checked each MLC leaf position for all control points in a VMAT arc relative to a reference ROI created by adding a small margin to PTV. For leaves opened outside the reference ROI, the method adjusted their positions to reduce dose to normal tissue while maintaining PTV coverage and satisfying leaf position constraints. The deliverability and dose accuracy of the method was verified by applying it to 15 VMAT plans which were delivered in five different linacs in our department. Dosimetric improvement of the proposed method was analyzed for another group of 16 randomly selected VMAT plans. The average gamma passing rate using a 3%/3 mm criteria for the verification group of VMAT plans was 98.3% and all passing rates were above our internal passing threshold. Dosimetric improvement was observed for the evaluation group of VMAT plans. The method can improve normal tissue protection for VMAT plans. It can be safely applied in routine clinic work.

Dosimetrical assessment of jaw tracking technique in volumetric modulated arc therapy for a sample of patients with lateralised targets

Abstract Introduction: In modulated radiotherapy treatments with the jaw tracking technique (JTT), the collimator jaws can dynamically follow the multileaf collimator apertures and reduce radiation leakage. This reduction protects normal tissue from unwanted doses. Previous research has highlighted the importance of defining which patients will benefit most from JTT. Besides, some authors have expressed their concerns about possible increases in monitor units (MUs). Treatments of patients with peripheral targets and isocentre located in the patient’s midline are of particular interest. The current work assessed the effect of JTT on these cases. Methods: JTT plans for thirty-two patients were compared to plans with the static jaws technique. The volumes of normal tissue receiving 5 Gy (V5), 10 Gy (V10) and 20 Gy (V20), mean dose (Dmean), target coverage parameters D95, D2% and Paddick’s conformity index (PCI) were compared. MUs were also registered for comparisons. The decrease in the jaws opening with JTT was correlated to the decrease in dose values in normal tissue. Results: Small decreases were observed in D95 and in D2% values, without statistical significance. A 5% average decrease in PCI values was noticed as well as significant decreases in V5, V10 and Dmean values, 9% on average. A 3% decrease in V20 was also observed. The number of MUs decreased by 2%. A significant correlation was found between the reduction of the secondary collimation opening areas and the dose delivered to normal tissue. Conclusions: JTT technique improved normal tissue protection in volumetric modulated arc therapy treatments for the patients included in the present study.

Computational systems biology approach for permanent tumor elimination and normal tissue protection using negative biasing: Experimental validation in malignant melanoma as case study.

Complete spontaneous tumor regression (without treatment) is well documented to occur in animals and humans as epidemiological analysis show, whereby the malignancy is permanently eliminated. We have developed a novel computational systems biology model for this unique phenomenon to furnish insight into the possibility of therapeutically replicating such regression processes on tumors clinically, without toxic side effects. We have formulated oncological informatics approach using cell-kinetics coupled differential equations while protecting normal tissue. We investigated three main tumor-lysis components: (ⅰ) DNA blockade factors, (ⅱ) Interleukin-2 (IL-2), and (ⅲ) Cytotoxic T-cells (CD8+ T). We studied the temporal variations of these factors, utilizing preclinical experimental investigations on malignant tumors, using mammalian melanoma microarray and histiocytoma immunochemical assessment. We found that permanent tumor regression can occur by: 1) Negative-Bias shift in population trajectory of tumor cells, eradicating them under first-order asymptotic kinetics, and 2) Temporal alteration in the three antitumor components (DNA replication-blockade, Antitumor T-lymphocyte, IL-2), which are respectively characterized by the following patterns: (a) Unimodal Inverted-U function, (b) Bimodal M-function, (c) Stationary-step function. These provide a time-wise orchestrated tri-phasic cytotoxic profile. We have also elucidated gene-expression levels corresponding to the above three components: (ⅰ) DNA-damage G2/M checkpoint regulation [genes: CDC2-CHEK], (ⅱ) Chemokine signaling: IL-2/15 [genes: IL2RG-IKT3], (ⅲ) T-lymphocyte signaling (genes: TRGV5-CD28). All three components quantitatively followed the same activation profiles predicted by our computational model (Smirnov-Kolmogorov statistical test satisfied, α = 5%). We have shown that the genes CASP7-GZMB are signatures of Negative-bias dynamics, enabling eradication of the residual tumor. Using the negative-biasing principle, we have furnished the dose-time profile of equivalent therapeutic agents (DNA-alkylator, IL-2, T-cell input) so that melanoma tumor may therapeutically undergo permanent extinction by replicating the spontaneous tumor regression dynamics.

Diuretic and Natriuretic Effects of Hesperidin, a Flavanone Glycoside, in Female and Male Hypertensive Rats

Hesperidin (HSP) is a major flavanone glycoside in citrus fruits, including sweet oranges and lemons. It demonstrates numerous pharmacological activities, such as antihypertensive effects and cardiac and kidney tissue protection. However, its effect on modulating renal function has yet to be properly explored. Female and male Wistar spontaneously hypertensive rats (SHR) were used to test the effect of HSP on renal function. The rats were divided into different groups, treated orally, and placed in metabolic cages for urine collection for 8 h. HSP, at doses of 0.3-3 mg/kg, led to an increase in urine volume in both female and male SHR. This effect was associated with increased Na+ elimination (3 mg/kg) without causing any change in K+ excretion or pH and conductivity values. When given HSP in combination with hydrochlorothiazide (HCTZ) or amiloride (AMLR), urine volume and Na+ elimination were significantly increased compared to the group that received only HSP. In relation to K+ excretion, the depleting effect of HCTZ and the sparing of AMLR prevailed in both groups. Pre-treatment with a non-selective cholinergic receptor antagonist, atropine, partially prevented HSP-induced diuresis and natriuresis in male SHR, but this effect was not demonstrated with the non-selective inhibitor of the enzyme cyclooxygenase, indomethacin. This study shows the diuretic action of HSP in hypertensive rats, an activity probably associated with the cholinergic pathway. Although various biological actions have already been defined for HSP, this pioneering research reveals its potential as a diuretic medicine.

Synthetic Reabsorbable Mesh (GalaFLEX) as Soft Tissue Adjunct in Breast Augmentation Revision Surgery.

A significant number of patients with a previous submuscular breast augmentation require a revision surgical procedure during their long-term follow-up period that involves changing the implant pocket from submuscular to subglandular. Reduced soft tissue thickness represents a major concern, discouraging surgeons from undertaking this approach. The aim of this study was to determine whether a synthetic resorbable mesh used as a supplemental covering device was safe and yielded improved soft tissue thickness and protection against capsular contracture in patients undergoing implant plane shift to subglandular. A retrospective review of 34 patients who underwent revision of a previous breast augmentation involving implant change in a subglandular pocket and upper pole GalaFLEX (Galatea Surgical, BD; Franklin Lakes, NJ) mesh coverage was conducted. Onset of minor and major complications was recorded during short- and medium-term follow-up. Patient satisfaction was assessed via an anonymous questionnaire administered 6 months postoperatively. During the follow-up period, which ranged from a minimum of 6 months to a maximum of 28 months, no minor or major complications were reported. In particular, no wrinkling/rippling or significant capsular contracture onset was observed. High levels of patient satisfaction were determined, according to self-reporting questionnaires. The initial results of this preliminary report from this case series demonstrate the safety of GalaFLEX as a supplemental device in terms of improved soft tissue coverage of the implant for complex revisional cases in breast augmentation.

Functional comorbidities and brain tissue changes before and after lung transplant in adults.

Adults undergoing lung transplant, as a lifesaving treatment for end stage lung disease, exhibit high levels of peri-operative neurocognitive dysfunction in multiple domains, including delirium, cognition, and autonomic deficits. These complications impact healthcare costs, quality of life, and patient outcomes. Post-operative symptoms likely result from loss of brain tissue integrity in sites mediating such regulatory functions. Our aim in this study was to examine peri-operative neurocognitive dysfunction and brain tissue changes after lung transplant in adults. We retrospectively examined the UCLA lung transplant database to identify 114 lung transplant patients with pre-operative clinical and neurocognitive data. Of 114 patients, 9 lung transplant patients had pre- and post-transplant brain magnetic resonance imaging. Clinical and neurocognitive data were summarized for all subjects, and brain tissue volume changes, using T1-weighted images, before and after transplant were examined. T1-weighted images were partitioned into gray matter (GM)-tissue type, normalized to a common space, smoothed, and the smoothed GM-volume maps were compared between pre- and post-transplant (paired t-tests; covariate, age; SPM12, p < 0.005). Increased comorbidities, including the diabetes mellitus (DM), hypertension, kidney disease, and sleep disordered breathing, as well as higher rates of neurocognitive dysfunction were observed in the lung transplant patients, with 41% experiencing post-operative delirium, 49% diagnosed with a mood disorder, and 25% of patients diagnosed with cognitive deficits, despite incomplete documentation. Similarly, high levels of delirium, cognitive dysfunction, and mood disorder were noted in a subset of patients used for brain MRI evaluation. Significantly decreased GM volumes emerged in multiple brain regions, including the frontal and prefrontal, parietal, temporal, bilateral anterior cingulate and insula, putamen, and cerebellar cortices. Adults undergoing lung transplant often show significant pre-operative comorbidities, including diabetes mellitus, hypertension, and chronic kidney disease, as well as neurocognitive dysfunction. In addition, patients with lung transplant show significant brain tissue changes in regions that mediate cognition, autonomic, and mood functions. The findings indicate a brain structural basis for many enhanced post-operative symptoms and suggest a need for brain tissue protection in adults undergoing lung transplant to improve health outcomes.

Effect of collateral level in CT angiography on clinical prognosis in stroke patients treated with mechanical thrombectomy after six hours

Objectives: Collaterals have an effect on the protection of penumbra tissue. We evaluated the effect of collaterals on single-phase computed tomography angiography (CTA) in patients with AIS treated with MT after 6 hours. Methods: We evaluated patients with ICA or M1 segment of MCA occlusion, time of symptom-groin puncture &gt;6 hours, having CTA before MT, modified Treatment In Cerebral Ischemia score (mTICI) 2b-3 recanalization after MT. Data of collateral levels, outcome measures, timings and other variables were collected from Turkish Interventional Neurology Database. The level of collaterals was assessed with modified Tan scale. Results: A total of 57 patients were included in our study. The median age was 64[56.5-75] years. The median NIHSS score at onset was 15[12-17.5] points. A total of 33 (57.9%) patients had good collaterals on CTA. Hypertension (HT) and diabetes mellitus (DM) rates were increased in the poor collaterals group. NIHSS scores decreased at the 24th hour in both good and poor collaterals groups. Twenty-two (66.7%) patients in the good collaterals group and 11 (45.8%) patients in the poor collaterals group had good clinical outcomes. However, there was not a significant difference (p=0.174, OR: 2.364; 95% CI: 0.802-6.697). Mortality rates were different in both groups, but the difference was not found to be significant (5[15.2%] versus 8[33.3%], p=0.124, OR:0.357; 95% CI: 0.1-1.278). Conclusion: Good collaterals on single-phase CTA was not associated with improved neurological outcomes in AIS patients treated after 6 hours.

Focusing COVID-19-associated mucormycosis: a major threat to immunocompromised COVID-19.

COVID-19 disease has been identified to cause remarkable increase of mucormycosis infection cases in India, with the majority of cases being observed in individuals recovering from COVID-19. Mucormycosis has emanated as an outcome of the recent COVID-19 pandemic outbreak as rapidly developing fatal illness which was acquired by Mucorales fungus which is a subcategory of molds known as mucormycetes. Mucormycosis is one of the serious, sporadic mycotic illnesses which is a great threat to immunocompromised COVID-19 patients and affects people of all ages, including children with COVID-19 infections. This is associated with tissue damaging property and, therefore, causes serious clinical complications and elevated death rate. The COVID-19-associated mucormycosis or "black fungus" are the terms used interchangeably. The rapid growth of tissue necrosis presenting as "rhino-orbital-cerebral, pulmonary, cutaneous, gastrointestinal, and disseminated disease" are various clinical forms of mucormycosis. The patient's prognosis and survival can be improved with proper surgeries using an endoscopic approach for local tissue protection in conjunction with course of appropriate conventional antifungal drug like Amphotericin-B and novel drugs like Rezafungin, encochleated Amphotericin B, Orolofim, and SCY-078 which have been explored in last few years. This review provides an overview of mucormycosis including its epidemiology, pathophysiology, risk factors, its clinical forms, and therapeutic approaches for disease management like antifungal therapy, surgical debridement, and iron chelators. The published patents and ongoing clinical trials related to mucormycosis have also been mentioned in this review.

Purinergic Signalling in the Cochlea

The mammalian cochlea is the sensory organ of hearing with a delicate, highly organised structure that supports unique operating mechanisms. ATP release from the secretory tissues of the cochlear lateral wall (stria vascularis) triggers numerous physiological responses by activating P2 receptors in sensory, supporting and neural tissues. Two families of P2 receptors, ATP-gated ion channels (P2X receptors) and G protein-coupled P2Y receptors, activate intracellular signalling pathways that regulate cochlear development, homeostasis, sensory transduction, auditory neurotransmission and response to stress. Of particular interest is a purinergic hearing adaptation, which reflects the critical role of the P2X2 receptor in adaptive cochlear response to elevated sound levels. Other P2 receptors are involved in the maturation of neural processes and frequency selectivity refinement in the developing cochlea. Extracellular ATP signalling is regulated by a family of surface-located enzymes collectively known as "ectonucleotidases" that hydrolyse ATP to adenosine. Adenosine is a constitutive cell metabolite with an established role in tissue protection and regeneration. The differential activation of A1 and A2A adenosine receptors defines the cochlear response to injury caused by oxidative stress, inflammation, and activation of apoptotic pathways. A1 receptor agonism, A2A receptor antagonism, and increasing adenosine levels in cochlear fluids all represent promising therapeutic tools for cochlear rescue from injury and prevention of hearing loss.

Radiotherapy with Helium Ions Has the Potential to Improve Both Endocrine and Neurocognitive Outcome in Pediatric Patients with Ependymoma

Ependymomas are the third most-frequent pediatric brain tumors. To prevent local recurrence, the resection site should be irradiated. Compared to photon radiation treatment, proton therapy often achieves even better results regarding target coverage and organ-sparing. Due to their physical properties, helium ions could further reduce side effects, providing better protection of healthy tissue despite similar target coverage. In our in silico study, 15 pediatric ependymoma patients were considered. All patients underwent adjuvant radiotherapeutic treatment with active-scanned protons at Heidelberg Ion Beam Therapy Center (HIT). Both helium ion and highly conformal IMRT plans were calculated to evaluate the potential dosimetric advantage of ion beam therapy compared to the current state-of-the-art photon-based treatments. To estimate the potential clinical benefit of helium ions, normal tissue complication probabilities (NTCP) were calculated. Target coverage was comparable in all three modalities. As expected, the integral dose absorbed by healthy brain tissue could be significantly reduced with protons by up to -48% vs. IMRT. Even compared to actively scanned protons, relative dose reductions for critical neuronal structures of up to another -39% were achieved when using helium ions. The dose distribution of helium ions is significantly superior when compared to proton therapy and IMRT due to the improved sparing of OAR. In fact, previous studies could clearly demonstrate that the dosimetric advantage of protons translates into a measurable clinical benefit for pediatric patients with brain tumors. Given the dose-response relationship of critical organs at risk combined with NTCP calculation, the results of our study provide a strong rationale that the use of helium ions has the potential to even further reduce the risk for treatment related sequelae.

Beneficial Effects of Melatonin on Periodontitis Management: Far More Than Oral Cavity

Periodontitis as a highly prevalent chronic infection/inflammatory disease can eventually lead to tooth loss and masticatory dysfunction. It also has a negative impact on general health and largely impairs quality of life. The tissue destruction during periodontitis is mainly caused by the excessive immune-inflammatory response; hence, how to modulate the host's reaction is of profound importance for effective periodontal treatment and tissue protection. Melatonin, as an endogenous hormone exhibiting multiple biological functions such as circadian rhythm regulation, antioxidant, and anti-inflammation, has been widely used in general healthcare. Notably, the past few years have witnessed increasing evidence for the application of melatonin as an adjunctive approach in the treatment of periodontitis and periodontitis-related systemic comorbidities. The detailed underlying mechanisms and more verification from clinical practice are still lacking, however, and further investigations are highly required. Importantly, it is essential to establish standard guidelines in the near future for the clinical administration of melatonin for periodontal health and general wellbeing.

Normothermic Ex Vivo Heart Perfusion with Mesenchymal Stem Cell-Derived Conditioned Medium Improves Myocardial Tissue Protection in Rat Donation after Circulatory Death Hearts.

Adopting hearts from donation after circulatory death (DCD) is a promising approach to enlarge the donor pool. Nevertheless, DCD hearts experience severe warm ischemia/reperfusion (I/R) injury. Recent studies have demonstrated that conditioned medium (CM) derived from bone marrow mesenchymal stem cells (BMSCs) has the potential of reducing organ I/R injury. Therefore, we investigated whether DCD heart preservation with normothermic ex vivo heart perfusion (EVHP) and BMSCs-CM treatment could alleviate myocardial warm I/R injury in the DCD hearts. We randomly divided donor rats into two groups: (1) DCD-Control group and (2) DCD-CM group. Before DCD heart preservation with the normothermic EVHP system for 105 minutes, rats suffered from a 25-minute warm ischemia injury in the DCD procedure. Vehicle or CM (300 μl) was added to the perfusate at the beginning of the perfusion process. The cardiac function of DCD hearts in the DCD-Control and DCD-CM groups was measured every 30 minutes. Besides, non-DCD hearts were harvested from the beating-heart rats. The antibody array demonstrated that the CM contained 14 bioactive factors involved in apoptosis, inflammation, and oxidative stress. Warm ischemia injury resulted in a significant increase in the level of oxidative stress, inflammation, and apoptosis in the DCD hearts of DCD-Control group. Furthermore, compared with the DCD-Control group, CM treatment increased the developed pressure, dP/dtmax and dP/dtmin of the left ventricular in the DCD hearts during a 90-minute EVHP. Moreover, the administration of CM attenuated the level of oxidative stress, inflammation, and apoptosis in the DCD hearts of the DCD-CM group. Normothermic EVHP combined with CM treatment can alleviate warm I/R injury in the DCD hearts by decreasing the level of oxidative stress, inflammatory response, and apoptosis, which might alleviate the shortage of donor hearts by adopting DCD hearts.

Remote Ischemic Pre-Conditioning (RIPC).

Ischemic pre-conditioning has been shown to protect hearts against ischemia/reperfusion (I/R)-induced cardiac injury. However, it is not feasible in clinic. Many researchers have tried to introduce brief I/R in skeletal muscle to mimic cardiac ischemic pre-conditioning, called remote ischemia pre-conditioning (RIPC). Studies from our group and other groups have shown that RIPC induces the release of cytokines from skeletal muscle (myokines) for tissue protection. Myokines play a central role in repair, inflammatory, and immune responses after injury. Thus, the detailed protocol for RIPC might be useful for researchers to study mechanisms underlying RIPC-mediated tissue protection and crosstalk. Here, we describe a detailed RIPC protocol and show MG53 secretion after RIPC into the blood.

Kidney diseases.

Dysregulation and accelerated activation of the alternative pathway (AP) of complement is known to cause or accentuate several pathologic conditions in which kidney injury leads to the appearance of hematuria and proteinuria and ultimately to the development of chronic renal failure. Multiple genetic and acquired defects involving plasma- and membrane-associated proteins are probably necessary to impair the protection of host tissues and to confer a significant predisposition to AP-mediated kidney diseases. This review aims to explore how our current understanding will make it possible to identify the mechanisms that underlie AP-mediated kidney diseases and to discuss the available clinical evidence that supports complement-directed therapies. Although the value of limiting uncontrolled complement activation has long been recognized, incorporating complement-targeted treatments into clinical use has proved challenging. Availability of anti-complement therapy has dramatically transformed the outcome of atypical hemolytic uremic syndrome, one of the most severe kidney diseases. Innovative drugs that directly counteract AP dysregulation have also opened new perspectives for the management of other kidney diseases in which complement activation is involved. However, gained experience indicates that the choice of drug should be tailored to each patient's characteristics, including clinical, histologic, genetic, and biochemical parameters. Successfully treating patients requires further research in the field and close collaboration between clinicians and researchers who have special expertise in the complement system.

Determination and comparison of dosimetric parameters of three-dimensional conformal radiotherapy, field in field, and intensity-modulated radiotherapy techniques in radiotherapy of breast conserving patients.

Three radiation therapy techniques for breast are common, namely three-dimensional conformal radiotherapy (3D-CRT), Field-in-Field (FIF), and Intensıty-Modulated Radıotherapy (IMRT). The purpose of this study was to determine and compare dosimetric parameters of three different treatment planning planning types; 3D-CRT, FIF, and IMRT in target and normal tissues after breast-conserving surgery. One hundred patients with left or right breast cancer cooperated in this study. They were divided into three categories (small, medium, and large size) based on breast volume. Three treatment planning techniques were carried out by planner for each patient in Prowess® 5.2 Treatment Planning System. The dosimetric parameters were obtained from dose-volume histograms using the CERR software (MATLAB Company, Washington, USA), which runs as an add-on in MATLAB software. 3D-CRT technique with the highest value of Dmax creates more hot spots than the other techniques in the tumor region (P = 0.013). IMRT and FIF showed the best uniformity compared to 3D-CRT in all groups with respect to the values of the parameters D98 and D2. IMRT provided the best coverage in the tumor compared to other methods (P < 0.001). 3D-CRT technique yielded a high volume receiving ≥107% of the prescription dose (P < 0.001). Among the three methods, the FIF method results in a lower dose to the lung for treatment based on the V5 and V20 parameters (P < 0.001). Homogeneity index for IMRT was better than FIF, as well as, conformity index (CI) for IMRT and FIF was better than 3D-CRT. IMRT and FIF plans offered excellent target coverage and uniformity, whereas FIF had better protection of healthy tissues. Thus FIF method is an efficient method to improve the quality of treatment for breast cancer patients.

Elucidating the neurological mechanism of the FLASH effect in juvenile mice exposed to hypofractionated radiotherapy.

Ultrahigh dose-rate radiotherapy (FLASH-RT) affords improvements in the therapeutic index by minimizing normal tissue toxicities without compromising antitumor efficacy compared to conventional dose-rate radiotherapy (CONV-RT). To investigate the translational potential of FLASH-RT to a human pediatric medulloblastoma brain tumor, we used a radiosensitive juvenile mouse model to assess adverse long-term neurological outcomes. Cohorts of 3-week-old male and female C57Bl/6 mice exposed to hypofractionated (2×10Gy, FLASH-RT or CONV-RT) whole brain irradiation and unirradiated controls underwent behavioral testing to ascertain cognitive status four months posttreatment. Animals were sacrificed 6months post-irradiation and tissues were analyzed for neurological and cerebrovascular decrements. The neurological impact of FLASH-RT was analyzed over a 6-month follow-up. FLASH-RT ameliorated neurocognitive decrements induced by CONV-RT and preserved synaptic plasticity and integrity at the electrophysiological (long-term potentiation), molecular (synaptophysin), and structural (Bassoon/Homer-1 bouton) levels in multiple brain regions. The benefits of FLASH-RT were also linked to reduced neuroinflammation (activated microglia) and the preservation of the cerebrovascular structure, by maintaining aquaporin-4 levels and minimizing microglia colocalized to vessels. Hypofractionated FLASH-RT affords significant and long-term normal tissue protection in the radiosensitive juvenile mouse brain when compared to CONV-RT. The capability of FLASH-RT to preserve critical cognitive outcomes and electrophysiological properties over 6-months is noteworthy and highlights its potential for resolving long-standing complications faced by pediatric brain tumor survivors. While care must be exercised before clinical translation is realized, present findings document the marked benefits of FLASH-RT that extend from synapse to cognition and the microvasculature.

An economic analysis of high milk somatic cell counts in dairy cattle in Chiang Mai, Thailand

Mastitis in dairy cattle can lead to significant financial losses due to a reduction in milk yield, the withdrawal period after treatment when milk cannot be sold, and an increase in somatic cell count (SCC) which can reduce the milk's per liter commercial value. Dairy cooperatives point at high-SCC problems as an important factor leading to suboptimal levels of milk quantity and quality. This study aims at describing farm characteristics and milking practices associated with high SCC, identifying risk factors, and assessing the economic loss due to high SCC in three dairy cooperatives in Chiang Mai, Thailand. A cross-sectional study was conducted on 208 dairy cattle farms from July to September 2018. Structured interviews were conducted to collect the data. Univariate and multivariate analyses were performed to determine the degree of association between factors and high SCC. A retrospective cost assessment of high SCC was conducted to estimate the losses in affected farms, and two potential coping strategies were assessed: (1) culling and (2) treating the cow. More than 12% of farms had high SCC (SCC > 500,000 cells/ml). Inappropriate vacuum pressure and inappropriate pulsation rate of milking machines were identified as significant risk factors according to the multiple logistic regression (P < 0.01). Both factors can decrease the natural protection of teat tissue, increasing the likelihood of bacterial infection. The average economic loss of high SCC in affected farms was 557 USD for a three-month period. When comparing response strategies (i.e., treatment vs. culling), treating the affected cow was found to be more cost-effective. With a probability of successful treatment of 54%, treating an affected cow leads to 1,158.7 USD in gains over 3 years (vs. doing nothing). The results of this economic analysis can be used to advocate to cooperatives the value of veterinarians and for investigating and treating cases of mastitis.

Neuropeptide regulation of non-redundant ILC2 responses at barrier surfaces.

Emerging studies indicate that cooperation between neurons and immune cells regulates antimicrobial immunity, inflammation and tissue homeostasis. For example, a neuronal rheostat provides excitatory or inhibitory signals that control the functions of tissue-resident group 2 innate lymphoid cells (ILC2s) at mucosal barrier surfaces1-4. ILC2s express NMUR1, a receptor for neuromedin U (NMU), which is a prominent cholinergic neuropeptide that promotes ILC2 responses5-7. However, many functions of ILC2s are shared with adaptive lymphocytes, including the production of type 2 cytokines8,9 and the release of tissue-protective amphiregulin (AREG)10-12. Consequently, there is controversy regarding whether innate lymphoid cells and adaptive lymphocytes perform redundant or non-redundant functions13-15. Here we generate a new genetic tool to target ILC2s for depletion or gene deletion in the presence of an intact adaptive immune system. Transgenic expression of iCre recombinase under the control of the mouse Nmur1 promoter enabled ILC2-specific deletion of AREG. This revealed that ILC2-derived AREG promotes non-redundant functions in the context of antiparasite immunity and tissue protection following intestinal damage and inflammation. Notably, NMU expression levels increased in inflamed intestinal tissues from both mice and humans, and NMU induced AREG production in mouse and human ILC2s. These results indicate that neuropeptide-mediated regulation of non-redundant functions of ILC2s is an evolutionarily conserved mechanism that integrates immunity and tissue protection.