Adrenal Vein Sampling for Primary Aldosteronism: Recommendations From the Australian and New Zealand Working Group.

Adrenal vein sampling (AVS) is the current recommended procedure for identifying unilateral subtypes of primary aldosteronism (PA), which are amenable to surgery with the potential for cure. AVS is a technically challenging procedure usually undertaken by interventional radiologists at tertiary centres. However, there are numerous variations in AVS protocols relating to patient preparation, sampling techniques and interpretation which may impact the success of AVS and patient care. To reduce practice variations, improve the success rates of AVS and optimise patient outcomes, we established an Australian and New Zealand AVS Working Group and developed evidence-based expert consensus recommendations for the preparation, performance and interpretation of AVS. These recommendations can be used by all healthcare professionals in a multidisciplinary team who look after the diagnosis and management of PA.

AMG 193, a Clinical Stage MTA-Cooperative PRMT5 Inhibitor, Drives Antitumor Activity Preclinically and in Patients With MTAP-Deleted Cancers.

One of the most robust synthetic lethal interactions observed in multiple functional genomic screens has been dependency on PRMT5 in cancer cells with MTAP deletion. We report the discovery of the clinical stage MTA-cooperative PRMT5 inhibitor AMG 193, which preferentially binds PRMT5 in the presence of MTA and has potent biochemical and cellular activity in MTAP-deleted cells across multiple cancer lineages. In vitro, PRMT5 inhibition induces DNA damage, cell cycle arrest, and aberrant alternative mRNA splicing in MTAP-deleted cells. In human cell line and patient-derived xenograft models, AMG 193 induces robust antitumor activity and is well tolerated with no impact on normal hematopoietic cell lineages. AMG 193 synergizes with chemotherapies or the KRAS G12C inhibitor sotorasib in vitro, and combination treatment in vivo significantly inhibits tumor growth. AMG 193 is demonstrating promising clinical activity, including confirmed partial responses in patients with MTAP-deleted solid tumors from an ongoing phase 1/2 study.

[Corrigendum] miR-382 inhibits migration and invasion by targeting ROR1 through regulating EMT in ovarian cancer.

Following the publication of the above article, an interested reader drew to the authors' attention that certain of the Transwell migration and invasion assay data panels shown in Figs. 3E and G and 7E and G on p. 1754 and 1757 respectively contained overlapping data panels, both within Fig. 3 and between Figs. 3 and 7, such that data which were intended to represent the results of differently performed experiments had apparently been derived from the same original sources. Specifically, the 'con' and 'pre-con' data panels in Fig. 3 were overlapping, as were the 'pre-con' and 'pcDNA.1-ROR1' panels comparing Fig. 3 with Fig. 7, and the Editorial Office subsequently pointed out to the authors that the 'con' and 'pre-con' data panels in Fig. 3E also contained an overlapping edge. After having examined their original data, the authors realized that these figures were inadvertently assembled incorrectly. The corrected versions of Figs. 3 and 7 are shown on the next page, now showing the correct data for the 'con' experiment in Fig. 3E, the 'pre-con' experiment in Fig. 3G, and the 'pcDNA.1-ROR1' panel in Fig. 7G. 'The authors are grateful to the Editor of International Journal of Oncology for granting them the opportunity to publish this corrigendum, and all the authors agree with its publication; furthermore, they apologize to the readership of the journal for any inconvenience caused. [International Journal of Oncology 48: 181-190, 2016; DOI: 10.3892/ijo.2015.3241].

A treatment-site-specific evaluation of commercial synthetic computed tomography solutions for proton therapy.

Background and purpose: Despite the superior dose conformity of proton therapy, the dose distribution is sensitive to daily anatomical changes, which can affect treatment accuracy. This study evaluated the dose recalculation accuracy of two synthetic computed tomography (sCT) generation algorithms in a commercial treatment planning system. Materials and methods: The evaluation was conducted for head-and-neck, thorax-and-abdomen, and pelvis sites treated with proton therapy. Thirty patients with two cone-beam computed tomography (CBCT) scans each were selected. The sCT images were generated from CBCT scans using two algorithms, Corrected CBCT (corrCBCT) and Virtual CT (vCT). Dose recalculations were performed based on these images for comparison with "ground truth" deformed CTs. Results: The choice of algorithm influenced dose recalculation accuracy, particularly in high dose regions. For head-and-neck cases, the corrCBCT method showed closer agreement with the "ground truth", while for thorax-and-abdomen and pelvis cases, the vCT algorithm yielded better results (mean percentage dose discrepancy of 0.6 %, 1.3 % and 0.5 % for the three sites, respectively, in the high dose region). Head-and-neck and pelvis cases exhibited excellent agreement in high dose regions (2 %/2 mm gamma passing rate >98 %), while thorax-and-abdomen cases exhibited the largest differences, suggesting caution in sCT algorithm usage for this site. Significant systematic differences were observed in the clinical target volume and organ-at-risk doses in head-and-neck and pelvis cases, highlighting the importance of using the correct algorithm. Conclusions: This study provided treatment site-specific recommendations for sCT algorithm selection in proton therapy. The findings offered insights for proton beam centers implementing adaptive radiotherapy workflows.

High-resolution functional mapping of RAD51C by saturation genome editing.

Pathogenic variants in RAD51C confer an elevated risk of breast and ovarian cancer, while individuals homozygous for specific RAD51C alleles may develop Fanconi anemia. Using saturation genome editing (SGE), we functionally assess 9,188 unique variants, including >99.5% of all possible coding sequence single-nucleotide alterations. By computing changes in variant abundance and Gaussian mixture modeling (GMM), we functionally classify 3,094 variants to be disruptive and use clinical truth sets to reveal an accuracy/concordance of variant classification >99.9%. Cell fitness was the primary assay readout allowing us to observe a phenomenon where specific missense variants exhibit distinct depletion kinetics potentially suggesting that they represent hypomorphic alleles. We further explored our exhaustive functional map, revealing critical residues on the RAD51C structure and resolving variants found in cancer-segregating kindred. Furthermore, through interrogation of UK Biobank and a large multi-center ovarian cancer cohort, we find significant associations between SGE-depleted variants and cancer diagnoses.

A Bilayer Polyurethane Patch with Sustained Growth Factor Release and Antibacteria for Re-epithelization of Large-Scale Oral Mucosal Defects.

In the field of oral and maxillofacial surgery, extensive oral soft-tissue injuries occur repeatedly in clinical practice; however, effective restorative materials are lacking. In this study, a biodegradable waterborne polyurethane patch featuring a mucosa bionic bilayer structure is presented. This patch consists of a porous scaffold layer that faces the lesion, incorporating a polydopamine coating to achieve sustained release of epidermal growth factors (EGFs) for mucosal defect reconstruction. Additionally, there is a dense barrier layer toward the oral cavity loaded with silver nanoparticles, which prevents bacteria from entering the wound and simultaneously acts as a physical barrier. This patch can sustainably release EGF in vitro for 2 weeks, thereby facilitating the proliferation and migration of HaCaT and L929 cells, while effectively killing common oral cavity bacteria. In a rabbit buccal mucosal full-thickness defect model, the patch demonstrates better efficacy than the clinical benchmark, decellularized extracellular matrix (dECM). It effectively reduces wound inflammation and significantly upregulates gene expression associated with epithelialization by activating the EGF/epidermal growth factor receptor (EGFR) pathway. These mechanisms promote the proliferation, differentiation, and migration of epithelial/keratinocyte cells, ultimately expediting mucosal defect healing and wound closure.

The Impact of Bariatric Surgery on Glutathione Synthesis in Individuals with Severe Obesity.

Glycine is deficient in individuals with obesity but improves following bariatric surgery. Glycine deficiency could impair glutathione (GSH) synthesis and worsen oxidative stress. We examined the impact of obesity-associated glycine deficiency and bariatric surgery on GSH synthesis. Twenty-one participants with severe obesity and twenty-one healthy weight controls were recruited. [1,2-13C2] glycine was infused to measure the erythrocyte (RBC) GSH synthesis rate. Participants with obesity underwent bariatric surgery, and 19 were restudied six months post-surgery. Compared to healthy weight controls, individuals with obesity had significantly lower concentrations of RBC GSH (2.43 ± 0.23 vs. 2.63 ± 0.26 mmol/L, p < 0.01). However, there were no differences in GSH fractional synthesis rate [78.0 (51.4-123.7) vs. 76.9 (49.3-110.1) % pool/day, p = 0.58] or absolute synthesis rate [1.85 (1.25-3.32) vs. 1.92 (1.43-3.03) mmol/L RBC/day, p = 0.97]. Despite a post-surgery increase in glycine concentration, no statistically significant changes in RBC GSH concentration or synthesis rates were detected. Further, the significant correlation between plasma glycine and RBC GSH concentration at baseline (r = 0.46, p < 0.01) was also lost following bariatric surgery. GSH concentration was significantly lower in participants with obesity, but bariatric surgery did not significantly increase GSH concentrations or synthesis rates.

Proton Beam Range and Charge Verification Using Multilayer Faraday Collector.

PURPOSE: A daily quality assurance (QA) check in proton therapy is ensuring that the range of each proton beam energy in water is accurate to 1 mm. This is important for ensuring that the tumor is adequately irradiated while minimizing damage to surrounding healthy tissue. It is also important to verify the total charge collected against the beam model. This work proposes a time-efficient method for verifying the range and total charge of proton beams at different energies using a multilayer Faraday collector (MLFC). METHODS: We used an MLFC-128-250 MeV comprising 128 layers of thin copper foils separated by thin insulating KaptonTM layers. Protons passing through the collector induce a charge on the metallic foils, which is integrated and measured by a multichannel electrometer. The charge deposition on the foils provides information about the beam range. RESULTS: Our results show that the proton beam range obtained using MLFC correlates closely with the range obtained from commissioning water tank measurements for all proton energies. Upon applying a range calibration factor, the maximum deviation is 0.4 g/cm2. The MLFC range showed no dependence on the number of monitor units and the source-to-surface distance. Range measurements collected over multiple weeks exhibited stability. The total charge collected agrees closely with the theoretical charge from the treatment planning system beam model for low- and mid-range energies. CONCLUSIONS: We have calibrated and commissioned the use of the MLFC to easily verify range and total charge of proton beams. This tool will improve the workflow efficiency of the proton QA.

Preparation and characterization of Iturin A/chitosan microcapsules and their application in post-harvest grape preservation.

Iturin A (IA) encapsulated in chitosan (CS) microcapsules (IA/CS) underwent thorough physicochemical characterization using thermogravimetric analysis (TGA), Fourier-transform infrared (FTIR) spectroscopy, and scanning electron microscopy (SEM). SEM confirmed the smooth, spherical morphology of the IA/CS microcapsules, while FTIR revealed complex intermolecular interactions between IA and CS. TGA demonstrated thermal stability within the 0-100 °C range, while particle size analysis revealed an average diameter of 553.4 nm. To evaluate IA/CS efficacy in post-harvest grape preservation, grapes were treated with sterile water (CK), 10 g/L CS, 0.1 g/L IA/CS, and 0.1 g/L chitosan empty microcapsules (CKM), then stored at 25 °C for 16 days. IA/CS significantly reduced decay and respiration intensity by 52.3 % and 23.8 %, respectively, compared to CK. IA/CS treatment also inhibited abscission rate, weight loss, firmness reduction, total soluble solids consumption, titratable acidity consumption, polyphenol oxidase, and peroxidase activities on par with CS treatment (p > 0.05), but performed better than CK (reductions of 26.9 %, 41.2 %, 25.8 %, 27.2 %, 24.2 %, 19.4 %, and 17.4 %, respectively) and CKM (p < 0.05). Sensory evaluation confirmed that IA/CS effectively suppressed decay, slowed post-harvest metabolic activity, and maintained grape quality. Therefore, IA/CS microcapsules offer a promising method for extending grape shelf life and preserving quality.

Saturation genome editing of BAP1 functionally classifies somatic and germline variants.

Many variants that we inherit from our parents or acquire de novo or somatically are rare, limiting the precision with which we can associate them with disease. We performed exhaustive saturation genome editing (SGE) of BAP1, the disruption of which is linked to tumorigenesis and altered neurodevelopment. We experimentally characterized 18,108 unique variants, of which 6,196 were found to have abnormal functions, and then used these data to evaluate phenotypic associations in the UK Biobank. We also characterized variants in a large population-ascertained tumor collection, in cancer pedigrees and ClinVar, and explored the behavior of cancer-associated variants compared to that of variants linked to neurodevelopmental phenotypes. Our analyses demonstrated that disruptive germline BAP1 variants were significantly associated with higher circulating levels of the mitogen IGF-1, suggesting a possible pathological mechanism and therapeutic target. Furthermore, we built a variant classifier with >98% sensitivity and specificity and quantify evidence strengths to aid precision variant interpretation.

Investigation of dosimetric effect of beam current fluctuations in synchrotron-based proton PBS continuous scanning.

Objective.In proton pencil beam scanning (PBS) continuous delivery, the beam is continuously delivered without interruptions between spots. For synchrotron-based systems, the extracted beam current exhibits a spill structure, and recent publications on beam current measurements have demonstrated significant fluctuations around the nominal values. These fluctuations potentially lead to dose deviations from those calculated assuming a stable beam current. This study investigated the dosimetric implications of such beam current fluctuations during proton PBS continuous scanning.Approach.Using representative clinical proton PBS plans, we performed simulations to mimic a worst-case clinical delivery environment with beam current varies from 50% to 250% of the nominal values. The simulations used the beam delivery parameters optimized for the best beam delivery efficiency of the upcoming particle therapy system at Mayo Clinic Florida. We reconstructed the simulated delivered dose distributions and evaluated the dosimetric impact of beam current fluctuations.Main results.Despite significant beam current fluctuations resulting in deviations at each spot level, the overall dose distributions were nearly identical to those assuming a stable beam current. The 1 mm/1% Gamma passing rate was 100% for all plans. Less than 0.2% root mean square error was observed in the planning target volume dose-volume histogram. Minimal differences were observed in all dosimetric evaluation metrics.Significance.Our findings demonstrate that with our beam delivery system and clinical planning practice, while significant beam current fluctuations may result in large local move monitor unit deviations at each spot level, the overall impact on the dose distribution is minimal.

A bioinspired injectable antioxidant hydrogel for prevention of postoperative adhesion.

Postoperative adhesions, a prevalent complication following abdominal surgery, affect 90% of patients undergoing abdominal surgical procedures. Currently, the primary approach to prevent postoperative adhesions involves physical isolation of the surgical site and surrounding tissues using a hydrogel; however, this method represents a rudimentary strategy. Herein, considering the impact of oxidative stress and free radicals on postoperative adhesion during wound healing, an injectable antioxidant hydrogel, named PU-OHA-D, was successfully synthesized, which is formed by the crosslinking of dopamine-modified oxidized hyaluronic acid (OHA-D) and dihydrazide-terminated polyurethane (PU-ADH) through hydrazone bonding. PU-OHA-D hydrogel possesses versatile characteristics such as rapid gel formation, injectability, self-repair capability and biodegradability. Additionally, they exhibit an excellent ability to clear free radicals and superior tissue adhesion. PU-OHA-D can be injected in situ to form a hydrogel to prevent abdominal wall-cecum adhesion. Importantly, it can effectively eliminate free radicals and inhibit oxidative stress at the wound site. Thereby, it leads to collagen physiological degradation and prevents the occurrence of postoperative adhesions. The bioinspired hydrogel demonstrates its great potential in preventing postoperative adhesion and promoting wound healing.

The Impact of Bariatric Surgery on Nitrogen Balance at Six months Post-surgery.

PURPOSE: Obesity, defined as abnormal or excessive fat accumulation that presents a risk to health, rose from 8.6 to 10.5% in Singapore's residents. Bariatric surgery, the primary treatment for severe obesity, induces fat and muscle loss. Adequate protein intake is vital for preventing muscle loss. This study examines nitrogen balance in individuals with obesity pre- and post-surgery. MATERIALS AND METHODS: Sixteen participants with severe obesity (BMI ≥ 32.5 kg/m2) undergoing bariatric surgery (14 sleeve gastrectomy, 2 Roux-en-Y gastric bypass) and 20 normal-weight controls (BMI < 25 kg/m2) were recruited. Nitrogen balance, calculated from dietary protein intake and urine nitrogen excretion, was assessed. Participants with obesity were re-evaluated 6 months post-surgery. Data were analyzed using parametric methods. RESULTS: At baseline, controls had a BMI of 20.8 ± 2.1 kg/m2; those with obesity had 40.9 ± 7.3. Daily calorie and protein intake for participants with obesity were not statistically significantly different from controls (calorie intake at 1467 ± 430 vs. 1462 ± 391 kcal, p = 0.9701, protein intake 74.2 ± 28.7 vs. 64.6 ± 18.3 g, p = 0.2289). Post-surgery, BMI, fat-free mass, fat mass, total energy intake, carbohydrate, and protein intake decreased significantly (p < 0.01). Protein oxidation and urine nitrogen excretion did not change after bariatric surgery. However, nitrogen balance significantly reduced from 2.62 ± 5.07 to - 1.69 ± 5.07 g/day (p = 0.025). CONCLUSION: Dietary protein intake is inadequate in individuals with obesity at 6 months post-bariatric surgery and contributes to a state of negative nitrogen balance.

Pituitary abscess: a descriptive analysis of a series of 19 patients-a multi-center experience.

OBJECTIVES: Pituitary abscess (PA) accounts for only 0.3-0.5% of sellar masses, and the lack of specific clinical symptoms makes diagnosing PA difficult without a surgical biopsy. In clinical practice, PA is often mistaken for cystic pituitary adenoma, craniopharyngioma, and Rathke's cyst. Thus, this study aims to investigate challenges in diagnosing PA and evaluate the importance of combining intraoperative surgery with postoperative antibiotic treatment. METHODS: We conducted a retrospective analysis of 19 patients diagnosed with PA through histopathology. All patients underwent transsphenoidal surgery (TSS) for pituitary adenomas after undergoing comprehensive preoperative evaluations, including routine tests, endocrine assay, and imaging examination. Furthermore, we compared different treatments for pituitary abscess (PA) to determine the most effective approach for achieving a favorable prognosis. RESULTS: The most prevalent symptom of PA was headache, especially in the frontal-temporal and vertex regions, ranging from mild to moderate severity. Hypopituitarism-related symptoms were also frequently observed, including hypaphrodisia, cold sensitivity, fatigue, weight loss, polyuria, and amenorrhea. Twelve patients exhibited abnormalities in endocrinology examinations. Diagnosing PA correctly is challenging. In our study, none of the patients were correctly diagnosed with PA prior to surgery, and many sellar lesions were misdiagnosed. The favorable prognosis was largely attributed to surgical intervention and active postoperative antibiotic therapy. CONCLUSIONS: Given the lack of clarity in preoperative diagnosis, typical intraoperative findings and effective antibiotics treatment are more indicative of the correct diagnosis than other tests. In terms of therapy, optimal surgical intervention and active postoperative antibiotic treatment contribute to resolving the challenges posed by PA.

Deformable anthropomorphic pelvis phantom for dose accumulation verification.

Objective.The validation of deformable image registration (DIR) for contour propagation is often done using contour-based metrics. Meanwhile, dose accumulation requires evaluation of voxel mapping accuracy, which might not be accurately represented by contour-based metrics. By fabricating a deformable anthropomorphic pelvis phantom, we aim to (1) quantify the voxel mapping accuracy for various deformation scenarios, in high- and low-contrast regions, and (2) identify any correlation between dice similarity coefficient (DSC), a commonly used contour-based metric, and the voxel mapping accuracy for each organ.Approach. Four organs, i.e. pelvic bone, prostate, bladder and rectum (PBR), were 3D printed using PLA and a Polyjet digital material, and assembled. The latter three were implanted with glass bead and CT markers within or on their surfaces. Four deformation scenarios were simulated by varying the bladder and rectum volumes. For each scenario, nine DIRs with different parameters were performed on RayStation v10B. The voxel mapping accuracy was quantified by finding the discrepancy between true and mapped marker positions, termed the target registration error (TRE). Pearson correlation test was done between the DSC and mean TRE for each organ.Main results. For the first time, we fabricated a deformable phantom purely from 3D printing, which successfully reproduced realistic anatomical deformations. Overall, the voxel mapping accuracy dropped with increasing deformation magnitude, but improved when more organs were used to guide the DIR or limit the registration region. DSC was found to be a good indicator of voxel mapping accuracy for prostate and rectum, but a comparatively poorer one for bladder. DSC > 0.85/0.90 was established as the threshold of mean TRE ⩽ 0.3 cm for rectum/prostate. For bladder, extra metrics in addition to DSC should be considered.Significance. This work presented a 3D printed phantom, which enabled quantification of voxel mapping accuracy and evaluation of correlation between DSC and voxel mapping accuracy.

Real-time gated proton therapy with a reduced source to imager distance: Commissioning and quality assurance.

INTRODUCTION: Real-time gated proton therapy (RGPT) is a motion management technique unique to the Hitachi particle therapy system. It uses pulsed fluoroscopy to track an implanted fiducial marker. There are currently no published guidelines on how to conduct the commissioning and quality assurance. In this work we reported on our centre's commissioning workflow and our daily and monthly QA procedures. METHODS: Six commissioning measurements were designed for RGPT. The measurements include imaging qualities, fluoroscopic exposures, RGPT marker tracking accuracy, temporal gating latency, fiducial marker tracking fidelity and an end-to-end proton dosimetry measurement. Daily QA consists of one measurement on marker localization accuracy. Four months daily QA trends are presented. Monthly QA consists of three measurementson the gating latency, fluoroscopy imaging quality and dosimetry verification of gating operation with RGPT. RESULTS: The RGPT was successfully commissioned in our centre. The air kerma rates were within 15 % from specifications and the marker tracking accuracies were within 0.245 mm. The gating latencies for turning the proton beam on and off were 119.5 and 50.0 ms respectively. The 0.4x10.0 mm2 Gold AnchorTM gave the best tracking results with visibility up to 30 g/cm2. Gamma analysis showed that dose distribution of a moving and static detectors had a passing rate of more than 95 % at 3 %/3mm. The daily marker localization QA results were all less than 0.2 mm. CONCLUSION: This work could serve as a good reference for other upcoming Hitachi particle therapy centres who are interested to use RGPT as their motion management solution.

The impact of obesity-associated glycine deficiency on the elimination of endogenous and exogenous metabolites via the glycine conjugation pathway.

Background: Glycine is an integral component of the human detoxification system as it reacts with potentially toxic exogenous and endogenously produced compounds and metabolites via the glycine conjugation pathway for urinary excretion. Because individuals with obesity have reduced glycine availability, this detoxification pathway may be compromised. However, it should be restored after bariatric surgery because of increased glycine production. Objective: To examine the impact of obesity-associated glycine deficiency on the glycine conjugation pathway. We hypothesize that the synthesis rates of acylglycines from endogenous and exogenous sources are significantly reduced in individuals with obesity but increase after bariatric surgery. Methods: We recruited 21 participants with class III obesity and 21 with healthy weight as controls. At baseline, [1,2-13C2] glycine was infused to study the glycine conjugation pathway by quantifying the synthesis rates of several acylglycines. The same measurements were repeated in participants with obesity six months after bariatric surgery. Data are presented as mean ± standard deviation, and p-value< 0.05 is considered statistically significant. Results: Baseline data of 20 participants with obesity were first compared to controls. Participants with obesity were significantly heavier than controls (mean BMI 40.5 ± 7.1 vs. 20.8 ± 2.1 kg/m2). They had significantly lower plasma glycine concentration (168 ± 30 vs. 209 ± 50 µmol/L) and slower absolute synthesis rates of acetylglycine, isobutyrylglycine, tigylglycine, isovalerylglycine, and hexanoylglycine. Pre- and post-surgery data were available for 16 participants with obesity. Post-surgery BMI decreased from 40.9 ± 7.3 to 31.6 ± 6.0 kg/m2. Plasma glycine concentration increased from 164 ± 26 to 212 ± 38 µmol/L) and was associated with significantly higher rates of excretion of acetylglycine, isobutyrylglycine, tigylglycine, isovalerylglycine, and hexanoylglycine. Benzoic acid (a xenobiotic dicarboxylic acid) is excreted as benzoylglycine; its synthesis rate was significantly slower in participants with obesity but increased after bariatric surgery. Conclusion: Obesity-associated glycine deficiency impairs the human body's ability to eliminate endogenous and exogenous metabolites/compounds via the glycine conjugation pathway. This impairment is ameliorated when glycine supply is restored after bariatric surgery. These findings imply that dietary glycine supplementation could treat obesity-associated metabolic complications due to the accumulation of intramitochondrial toxic metabolites. Clinical trial registration: https://clinicaltrials.gov/study/NCT04660513, identifier NCT04660513.

The allostery and modification of hGHRH molecules and specific dimer produced significant fertility effect by proliferating and activating in-situ ovarian mesenchymal stem cells.

The negative coordination of growth hormone secretagogue receptor (GHS-R) and growth hormone-releasing hormone receptor (GHRH-R) involves in the repair processes of cellular injury. The allosteric U- or H-like modified GHRH dimer Grinodin and 2Y were comparatively evaluated in normal Kunming mice and hamster infertility models induced by CPA treatment. 1-3-9 µg of Grinodin or 2Y per hamster stem-cell-exhaustion model was subcutaneously administered once a week, respectively inducing 75-69-46 or 45-13-50 % of birth rates. In comparison, the similar mole of human menopausal gonadotropin (hMG) or human growth hormone (hGH) was administered once a day but caused just 25 or 20 % of birth rates. Grinodin induced more big ovarian follicles and corpora lutea than 2Y, hMG, hGH. The hMG-treated group was observed many distorted interstitial cells and more connective tissues and the hGH-treated group had few ovarian follicles. 2Y had a plasma lifetime of 21 days and higher GH release in mice, inducing lower birth rate and stronger individual specificity in reproduction as well as only promoting the proliferation of mesenchymal-stem-cells (MSCs) in the models. In comparison, Grinodin had a plasma lifetime of 30 days and much lower GH release in mice. It significantly promoted the proliferation and activation of ovarian MSCs together with the development of follicles in the models by increasing Ki67 and GHS-R expressions, and decreasing GHRH-R expression in a dose-dependent manner. However, the high GH and excessive estrogen levels in the models showed a dose-dependent reduction in fertility. Therefore, unlike 2Y, the low dose of Grinodin specifically shows low GHS-R and high GHRH-R expressions thus evades GH and estrogen release and improves functions of organs, resulting in an increase of fertility.

Repurposing DailyQA3 for an efficient and spot position sensitive daily quality assurance tool for proton therapy.

INTRODUCTION: Daily quality assurance is an integral part of a radiotherapy workflow to ensure the dose is delivered safely and accurately to the patient. It is performed before the first treatment of the day and needs to be time and cost efficient for a multiple gantries proton center. In this study, we introduced an efficient method to perform QA for output constancy, range verification, spot positioning accuracy and imaging and proton beam isocenter coincidence with DailyQA3. METHODS: A stepped acrylic block of specific dimensions is fabricated and placed on top of the DailyQA3 device. Treatment plans comprising of two different spread-out Bragg peaks and five individual spots of 1.0 MU each are designed to be delivered to the device. A mathematical framework to measure the 2D distance between the detectors and individual spot is introduced and play an important role in realizing the spot positioning and centering QA. Lastly, a 5 months trends of the QA for two gantries are presented. RESULTS: The outputs are monitored by two ion chambers in the DailyQA3 and a tolerance of ± 3 % $ \pm 3\% $ are used. The range of the SOBPs are monitored by the ratio of ion chamber signals and a tolerance of ± 1 mm $ \pm 1\ {\mathrm{mm}}$ is used. Four diodes at ± 10 cm $ \pm 10\ {\mathrm{cm}}$ from the central ion chambers are used for spot positioning QA, while the central ion chamber is used for imaging and proton beam isocenter coincidence QA. Using the framework, we determined the absolute signal threshold corresponding to the offset tolerance between the individual proton spot and the detector. A 1.5 mm $1.5\ {\mathrm{mm}}$ tolerances are used for both the positioning and centering QA. No violation of the tolerances is observed in the 5 months trends for both gantries. CONCLUSION: With the proposed approach, we can perform four QA items in the TG224 within 10 min.

Recombinant human collagen I/carboxymethyl chitosan hydrogel loaded with long-term released hUCMSCs derived exosomes promotes skin wound repair.

BACKGROUND: Stem cell exosomes are beneficial in accelerating wound repair. However, the therapeutic function is limited due to its rapid clearance in vivo. To improve the functionality of exosomes in cutaneous wound healing, a novel hydrogel was designed and fabricated by recombinant human collagen I and carboxymethyl chitosan loaded with exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSCs), named as the rhCol I/CMC-Exos hydrogel. METHODS: Exosomes were extracted from hUCMSCs and were characterizated by TEM (Transmission Electron Microscopy), and biomarker detection. The rhCol I hydrogel, rhCol I/carboxymethyl chitosan (rhCol I/CMC) hydrogel and the rhCol I/CMC-Exos hydrogel composites were cross-linked by genipin. These materials were assessed and compared for their physical characteristics, including cross-sectional morphology, porosity, pore distribution, and hydrophilicity. Cell biocompatibility on biomaterials was investigated using scanning electron microscopy and CFDA staining, as well as assessed in vivo through histological examination of major organs in mice. Effects of the hydrogel composite on wound healing were further evaluated by using the full-thickness skin defect mice model. RESULTS: Successful extraction of hUCMSCs-derived exosomes was confirmed by TEM，Western Blotting and flow cytometry. The synthesized rhCol I/CMC-Exos hydrogel composite exhibited cytocompatibility and promoted cell growth in vitro. The rhCol I/CMC-Exos hydrogel showed sustained release of exosomes. In the mice full skin-defects model, the rhCol I/CMC-Exos-treated group showed superior wound healing efficiency, with 15 % faster wound closure compared to controls. Histological examinations revealed thicker dermis formation and more balanced collagen deposition in wounds treated with rhCol I/CMC-Exos hydrogel. Mechanistically, the application of rhCol I/CMC-Exos hydrogel increased fibroblasts proliferation, alleviated inflammation responses as well as promoted angiogenesis, thereby was beneficial in promoting skin wound healing and regeneration. CONCLUSION: Our study, for the first time, introduced recombinant human Collagen I in fabricating a novel hydrogel loaded with hUCMSCs-derived exosomes, which effectively promoted skin wound closure and regeneration, demonstrating a great potential in severe skin wound healing treatment.