miR-146a Decreases Inflammation and ROS Production in Aged Dermal Fibroblasts.

Aging is associated with a decline in the functionality of various cell types, including dermal fibroblasts, which play a crucial role in maintaining skin homeostasis and wound healing. Chronic inflammation and increased reactive oxygen species (ROS) production are hallmark features of aging, contributing to impaired wound healing. MicroRNA-146a (miR-146a) has been implicated as a critical regulator of inflammation and oxidative stress in different cell types, yet its role in aged dermal fibroblasts and its potential relevance to wound healing remains poorly understood. We hypothesize that miR-146a is differentially expressed in aged dermal fibroblasts and that overexpression of miR-146a will decrease aging-induced inflammatory responses and ROS production. Primary dermal fibroblasts were isolated from the skin of 17-week-old (young) and 88-week-old (aged) mice. Overexpression of miR-146a was achieved through miR-146a mimic transfection. ROS were detected using a reliable fluorogenic marker, 2,7-dichlorofluorescin diacetate. Real-time PCR was used to quantify relative gene expression. Our investigation revealed a significant reduction in miR-146a expression in aged dermal fibroblasts compared to their younger counterparts. Moreover, aged dermal fibroblasts exhibited heightened levels of inflammatory responses and increased ROS production. Importantly, the overexpression of miR-146a through miR-146a mimic transfection led to a substantial reduction in inflammatory responses through modulation of the NF-kB pathway in aged dermal fibroblasts. Additionally, the overexpression of miR-146a led to a substantial decrease in ROS production, achieved through the downregulation of NOX4 expression in aged dermal fibroblasts. These findings underscore the pivotal role of miR-146a in mitigating both inflammatory responses and ROS production in aged dermal fibroblasts, highlighting its potential as a therapeutic target for addressing age-related skin wound healing.

Cxcr3 constrains pancreatic cancer dissemination through instructing T cell fate.

Pancreatic ductal adenocarcinoma (PDA) is a lethal and metastatic malignancy resistant to therapy. Elucidating how pancreatic tumor-specific T cells differentiate and are maintained in vivo could inform novel therapeutic avenues to promote T cell antitumor activity. Here, we show that the spleen is a critical site harboring tumor-specific CD8 T cells that functionally segregate based on differential Cxcr3 and Klrg1 expression. Cxcr3+ Klrg1- T cells express the memory stem cell marker Tcf1, whereas Cxcr3-Klrg1 + T cells express GzmB consistent with terminal differentiation. We identify a Cxcr3+ Klrg1+ intermediate T cell subpopulation in the spleen that is highly enriched for tumor specificity. However, tumor-specific T cells infiltrating primary tumors progressively downregulate both Cxcr3 and Klrg1 while upregulating exhaustion markers PD-1 and Lag-3. We show that antigen-specific T cell infiltration into PDA is Cxcr3 independent. Further, Cxcr3-deficiency results in enhanced antigen-specific T cell IFNγ production in primary tumors, suggesting that Cxcr3 promotes loss of effector function. Ultimately, however, Cxcr3 was critical for mitigating cancer cell dissemination following immunotherapy with CD40 agonist + anti-PD-L1 or T cell receptor engineered T cell therapy targeting mesothelin. In the absence of Cxcr3, splenic Klrg1 + GzmB + antitumor T cells wain while pancreatic cancer disseminates suggesting a role for these cells in eliminating circulating metastatic tumor cells. Intratumoral myeloid cells are poised to produce Cxcl10, whereas splenic DC subsets produce Cxcl9 following immunotherapy supporting differential roles for these chemokines on T cell differentiation. Together, our study supports that Cxcr3 mitigates tumor cell dissemination by impacting peripheral T cell fate rather than intratumoral T cell trafficking.

CD40 Agonist Overcomes T Cell Exhaustion Induced by Chronic Myeloid Cell IL-27 Production in a Pancreatic Cancer Preclinical Model.

Pancreatic cancer is a particularly lethal malignancy that resists immunotherapy. In this study, using a preclinical pancreatic cancer murine model, we demonstrate a progressive decrease in IFN-γ and granzyme B and a concomitant increase in Tox and IL-10 in intratumoral tumor-specific T cells. Intratumoral myeloid cells produced elevated IL-27, a cytokine that correlates with poor patient outcome. Abrogating IL-27 signaling significantly decreased intratumoral Tox+ T cells and delayed tumor growth yet was not curative. Agonistic αCD40 decreased intratumoral IL-27-producing myeloid cells, decreased IL-10-producing intratumoral T cells, and promoted intratumoral Klrg1+Gzmb+ short-lived effector T cells. Combination agonistic αCD40+αPD-L1 cured 63% of tumor-bearing animals, promoted rejection following tumor rechallenge, and correlated with a 2-log increase in pancreas-residing tumor-specific T cells. Interfering with Ifngr1 expression in nontumor/host cells abrogated agonistic αCD40+αPD-L1 efficacy. In contrast, interfering with nontumor/host cell Tnfrsf1a led to cure in 100% of animals following agonistic αCD40+αPD-L1 and promoted the formation of circulating central memory T cells rather than long-lived effector T cells. In summary, we identify a mechanistic basis for T cell exhaustion in pancreatic cancer and a feasible clinical strategy to overcome it.

Homologous Recombination Deficiency: Concepts, Definitions, and Assays.

BACKGROUND: Homologous recombination deficiency (HRD) is a phenotype that is characterized by the inability of a cell to effectively repair DNA double-strand breaks using the homologous recombination repair (HRR) pathway. Loss-of-function genes involved in this pathway can sensitize tumors to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapy, which target the destruction of cancer cells by working in concert with HRD through synthetic lethality. However, to identify patients with these tumors, it is vital to understand how to best measure homologous repair (HR) status and to characterize the level of alignment in these measurements across different diagnostic platforms. A key current challenge is that there is no standardized method to define, measure, and report HR status using diagnostics in the clinical setting. METHODS: Friends of Cancer Research convened a consortium of project partners from key healthcare sectors to address concerns about the lack of consistency in the way HRD is defined and methods for measuring HR status. RESULTS: This publication provides findings from the group's discussions that identified opportunities to align the definition of HRD and the parameters that contribute to the determination of HR status. The consortium proposed recommendations and best practices to benefit the broader cancer community. CONCLUSION: Overall, this publication provides additional perspectives for scientist, physician, laboratory, and patient communities to contextualize the definition of HRD and various platforms that are used to measure HRD in tumors.

PIK3CA mutation status, progression and survival in advanced HR + /HER2- breast cancer: a meta-analysis of published clinical trials.

BACKGROUND: Approximately 40% of hormone receptor positive/human epidermal receptor 2 negative (HR + /HER2-) metastatic breast cancer (mBC) patients harbor phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations. However, associations between PIK3CA mutation status and clinical outcomes among patients with HR + /HER2- mBC have been heterogeneous across clinical trials. This meta-analysis was conducted to survey recently available trial data to assess the prognostic effects of PIK3CA among patients with HR + /HER2- mBC.  METHODS: Randomized clinical trials reporting progression-free survival (PFS) or overall survival (OS) stratified by PIK3CA status in HR + /HER2- mBC were identified via systematic literature review. Trial arms receiving phosphatidylinositol 3-kinase (PI3K)-targeted therapies were excluded. Meta-regression analysis was used to estimate the association between PIK3CA status and PFS and OS among included studies. RESULTS: The analyzed data included 3,219 patients from 33 study arms across 11 trials (PIK3CA mutated: 1,386, wild type: 1,833). PIK3CA mutation was associated with shorter median PFS (difference [95% CI] (months): -1.8 [-3.4, -0.1], I2 = 35%) and shorter median OS (-8.4 [-13.4, -3.5], I2 = 58%, N = 1,545). Findings were similar for PFS rates at 6 months (odds ratio [95% CI]: 0.74 [0.59, 0.94], I2 = 42%, N = 3,160) and 12 months (0.76 [0.59, 0.99], I2 = 42%, N = 2,468) and directionally consistent but not statistically significant at 18 months (N = 1,726). CONCLUSIONS: Pooling evidence across multiple studies, PIK3CA mutation was associated with shorter PFS and OS. These findings suggest a negative prognostic value of PIK3CA mutations in patients with HR + /HER2- mBC.

Sounds of sickness: can people identify infectious disease using sounds of coughs and sneezes?

Cough, cough. Is that person sick, or do they just have a throat tickle? A growing body of research suggests pathogen threats shape key aspects of human sociality. However, less research has investigated specific processes involved in pathogen threat detection. Here, we examine whether perceivers can accurately detect pathogen threats using an understudied sensory modality-sound. Participants in four studies judged whether cough and sneeze sounds were produced by people infected with a communicable disease or not. We found no evidence that participants could accurately identify the origins of these sounds. Instead, the more disgusting they perceived a sound to be, the more likely they were to judge that it came from an infected person (regardless of whether it did). Thus, unlike research indicating perceivers can accurately diagnose infection using other sensory modalities (e.g. sight, smell), we find people overperceive pathogen threat in subjectively disgusting sounds.

Image artifacts caused by incorrect bowtie filters in cone-beam CT image-guided radiotherapy.

Certain models of cone beam computed tomography (CBCT) image-guided radiotherapy (IGRT) systems require manually placing the appropriate bowtie filter according to the relevant imaging protocol. Inadvertently using a wrong bowtie filter or no bowtie filter could cause unexpected image artifacts. In this work, CBCT image artifact patterns caused by different bowtie filter placement were evaluated. CBCT images of CT phantoms, that is, a Body Norm phantom, a Catphan® phantom and an anthropomorphic RANDO® phantom, were acquired at a Varian Trilogy® unit with an On-Board Imager® (OBI) system. Three image acquisition protocols were evaluated. For Standard Head protocol, half-fan bowtie and no bowtie filter were studied for comparison with the correct full-fan bowtie acquisition. For Pelvis and Low-Dose Thorax protocols, full-fan bowtie and no bowtie were studied for comparison with the correct half-fan bowtie acquisition. In addition, the possibility of reversed direction half-fan bowtie was also discussed. All possible scenarios of bowtie filter misplacement caused distinct artifacts regardless of protocols. These artifact patterns are different from the characteristic crescent artifact when correct bowtie filter was placed. Based on the artifact patterns described in this study we recommend reviewing image artifacts at time of image acquisition. If unexpected artifacts appear in the CBCT images, one should verify the correct placement of the bowtie filter and retake the image if necessary. However, it should also be stressed that using a wrong bowtie filter or forgetting to place the bowtie filter can cause increased patient dose. It is always a good practice to verify the bowtie filter placement before acquiring CBCT images for image-guided radiotherapy.

Improved dose homogeneity using electronic compensation technique for total body irradiation.

In total body irradiation (TBI) utilizing large parallel-opposed fields, the manual placement of lead compensators has conventionally been used to compensate for the varying thickness throughout the body. The goal of this study is to pursue utilizing the modern electronic compensation (E-comp) technique to more accurately deliver dose to TBI patients. Bilateral parallel-opposed TBI treatment plans were created using E-comp for 15 patients for whom CT data had been previously acquired. A desirable fluence pattern was manually painted within each field to yield a uniform dose distribution. The conventional compensation technique was simulated within the treatment planning system (TPS) using a field-in-field (FIF) method. This allows for a meaningful evaluation of the E-comp technique in comparison to the conventional method. Dose-volume histograms (DVH) were computed for all treatment plans. The mean total body dose using E-comp deviates from the prescribed dose (4 Gy) by an average of 2.4%. The mean total body dose using the conventional compensation deviates from the prescribed dose by an average of 4.5%. In all cases, the mean body dose calculated using E-comp technique deviates less than 10% from that of conventional compensation. The average reduction in maximum dose using E-comp compared to that of the conventional method was 30.3% ± 6.6% (standard deviation). In all cases, the s-index for the E-comp technique was lower (10.5% ± 0.7%) than that of the conventional method (15.8% ± 4.4%), indicating a more homogenous dose distribution. In conclusion, a large reduction in maximum body dose can be seen using the proposed E-comp technique while still producing a mean body dose that accurately complies with the prescription dose. Dose homogeneity was quantified using s-index which demonstrated a reduction in hotspots with E-comp technique. Electronic compensation technique is capable of more accurately delivering a total body dose compared to conventional methods.

Effects of collimator angle, couch angle, and starting phase on motion-tracking dynamic conformal arc therapy (4D DCAT).

PURPOSE: The aim of this study was to find an optimized configuration of collimator angle, couch angle, and starting tracking phase to improve the delivery performance in terms of MLC position errors, maximal MLC leaf speed, and total beam-on time of DCAT plans with motion tracking (4D DCAT). METHOD AND MATERIALS: Nontracking conformal arc plans were first created based on a single phase (maximal exhalation phase) of a respiratory motion phantom with a spherical target. An ideal model was used to simulate the target motion in superior-inferior (SI), anterior-posterior (AP), and left-right (LR) dimensions. The motion was decomposed to the MLC leaf position coordinates for motion compensation and generating 4D DCAT plans. The plans were studied with collimator angle ranged from 0° to 90°; couch angle ranged from 350°(-10°) to 10°; and starting tracking phases at maximal inhalation (θ=π/2) and exhalation (θ=0) phases. Plan performance score (PPS) evaluates the plan complexity including the variability in MLC leaf positions, degree of irregularity in field shape and area. PPS ranges from 0 to 1, where low PPS indicates a plan with high complexity. The 4D DCAT plans with the maximal and the minimal PPS were selected and delivered on a Varian TrueBeam linear accelerator. Gafchromic-EBT3 dosimetry films were used to measure the dose delivered to the target in the phantom. Gamma analysis for film measurements with 90% passing rate threshold using 3%/3 mm criteria and trajectory log files were analyzed for plan delivery accuracy evaluation. RESULTS: The maximal PPS of all the plans was 0.554, achieved with collimator angle at 87°, couch angle at 350°, and starting phase at maximal inhalation (θ=π/2). The maximal MLC leaf speed, MLC leaf errors, total leaf travel distance, and beam-on time were 20 mm/s, 0.39 ± 0.16 mm, 1385 cm, and 157 s, respectively. The starting phase, whether at maximal inhalation or exhalation had a relatively small contribution to PPS (0.01 ± 0.05). CONCLUSIONS: By selecting collimator angle, couch angle, and starting tracking phase, 4D DCAT plans with the maximal PPS demonstrated less MLC leaf position errors, lower maximal MLC leaf speed, and shorter beam-on time which improved the performance of 4D motion-tracking DCAT delivery.

The dose penumbra of a custom-made shield used in hemibody skin electron irradiation.

We report our technique for hemibody skin electron irradiation with a custom-made plywood shield. The technique is similar to our clinical total skin electron irradiation (TSEI), performed with a six-pair dual field (Stanford technique) at an extended source-to-skin distance (SSD) of 377 cm, with the addition of a plywood shield placed at 50 cm from the patient. The shield is made of three layers of stan-dard 5/8'' thick plywood (total thickness of 4.75 cm) that are clamped securely on an adjustable-height stand. Gafchromic EBT3 films were used in assessing the shield's transmission factor and the extent of the dose penumbra region for two different shield-phantom gaps. The shield transmission factor was found to be about 10%. The width of the penumbra (80%-to-20% dose falloff) was measured to be 12 cm for a 50 cm shield-phantom gap, and reduced slightly to 10 cm for a 35 cm shield-phantom gap. In vivo dosimetry of a real case confirmed the expected shielded area dose.

Evaluation of dosimetric effect caused by slowing with multi-leaf collimator (MLC) leaves for volumetric modulated arc therapy (VMAT).

BACKGROUND: This study is to report 1) the sensitivity of intensity modulated radiation therapy (IMRT) QA method for clinical volumetric modulated arc therapy (VMAT) plans with multi-leaf collimator (MLC) leaf errors that will not trigger MLC interlock during beam delivery; 2) the effect of non-beam-hold MLC leaf errors on the quality of VMAT plan dose delivery. MATERIALS AND METHODS: Eleven VMAT plans were selected and modified using an in-house developed software. For each control point of a VMAT arc, MLC leaves with the highest speed (1.87-1.95 cm/s) were set to move at the maximal allowable speed (2.3 cm/s), which resulted in a leaf position difference of less than 2 mm. The modified plans were considered as 'standard' plans, and the original plans were treated as the 'slowing MLC' plans for simulating 'standard' plans with leaves moving at relatively lower speed. The measurement of each 'slowing MLC' plan using MapCHECK®2 was compared with calculated planar dose of the 'standard' plan with respect to absolute dose Van Dyk distance-to-agreement (DTA) comparisons using 3%/3 mm and 2%/2 mm criteria. RESULTS: All 'slowing MLC' plans passed the 90% pass rate threshold using 3%/3 mm criteria while one brain and three anal VMAT cases were below 90% with 2%/2 mm criteria. For ten out of eleven cases, DVH comparisons between 'standard' and 'slowing MLC' plans demonstrated minimal dosimetric changes in targets and organs-at-risk. CONCLUSIONS: For highly modulated VMAT plans, pass rate threshold (90%) using 3%/3mm criteria is not sensitive in detecting MLC leaf errors that will not trigger the MLC leaf interlock. However, the consequential effects of non-beam hold MLC errors on target and OAR doses are negligible, which supports the reliability of current patient-specific IMRT quality assurance (QA) method for VMAT plans.

TBI lung dose comparisons using bilateral and anteroposterior delivery techniques and tissue density corrections.

This study compares lung dose distributions for two common techniques of total body photon irradiation (TBI) at extended source-to-surface distance calculated with, and without, tissue density correction (TDC). Lung dose correction factors as a function of lateral thorax separation are approximated for bilateral opposed TBI (supine), similar to those published for anteroposterior-posteroanterior (AP-PA) techniques in AAPM Report 17 (i.e., Task Group 29). 3D treatment plans were created retrospectively for 24 patients treated with bilateral TBI, and for whom CT data had been acquired from the head to the lower leg. These plans included bilateral opposed and AP-PA techniques- each with and without - TDC, using source-to-axis distance of 377 cm and largest possible field size. On average, bilateral TBI requires 40% more monitor units than AP-PA TBI due to increased separation (26% more for 23 MV). Calculation of midline thorax dose without TDC leads to dose underestimation of 17% on average (standard deviation, 4%) for bilateral 6 MV TBI, and 11% on average (standard deviation, 3%) for 23 MV. Lung dose correction factors (CF) are calculated as the ratio of midlung dose (with TDC) to midline thorax dose (without TDC). Bilateral CF generally increases with patient separation, though with high variability due to individual uniqueness of anatomy. Bilateral CF are 5% (standard deviation, 4%) higher than the same corrections calculated for AP-PA TBI in the 6 MV case, and 4% higher (standard deviation, 2%) for 23 MV. The maximum lung dose is much higher with bilateral TBI (up to 40% higher than prescribed, depending on patient anatomy) due to the absence of arm tissue blocking the anterior chest. Dose calculations for bilateral TBI without TDC are incorrect by up to 24% in the thorax for 6 MV and up to 16% for 23 MV. Bilateral lung CF may be calculated as 1.05 times the values published in Table 6 of AAPM Report 17, though a larger patient pool is necessary to better quantify this trend. Bolus or customized shielding will reduce lung maximum dose in the anterior thorax.

Gluteal silicone injections leading to extensive filler migration with induration and arthralgia.

Silicone injections have been used for cosmetic soft tissue augmentation for over five decades with documented consequences both systemic and dermatologic. We present a case of extensive filler migration causing bilateral lower extremity woody induration in a 53 year old Hispanic woman. She presented with a multi-year history of progressive joint stiffening at the knees, accompanied by induration and pain of the bilateral lower extremities. The patient had received two injections of an unknown substance placed into her bilateral gluteals 11 years prior. MRI indicated an infiltrative process of both lower extremities and pathology was consistent with migration of injected tissue augmentation material, most likely silicone. Due to the extent of involvement the patient was started on a trial of doxycycline 100 mg PO BID.

The AAPM/ASTRO 2023 Core Physics Curriculum for Radiation Oncology Residents.

PURPOSE: The American Association of Physicists in Medicine Radiation Oncology Medical Physics Education Subcommittee (ROMPES) has updated the radiation oncology physics core curriculum for medical residents in the radiation oncology specialty. METHODS AND MATERIALS: Thirteen physicists from the United States and Canada involved in radiation oncology resident education were recruited to ROMPES. The group included doctorates and master's of physicists with a range of clinical or academic roles. Radiation oncology physician and resident representatives were also consulted in the development of this curriculum. In addition to modernizing the material to include new technology, the updated curriculum is consistent with the format of the American Board of Radiology Physics Study Guide Working Group to promote concordance between current resident educational guidelines and examination preparation guidelines. RESULTS: The revised core curriculum recommends 56 hours of didactic education like the 2015 curriculum but was restructured to provide resident education that facilitates best clinical practice and scientific advancement in radiation oncology. The reference list, glossary, and practical modules were reviewed and updated to include recent literature and clinical practice examples. CONCLUSIONS: ROMPES has updated the core physics curriculum for radiation oncology residents. In addition to providing a comprehensive curriculum to promote best practice for radiation oncology practitioners, the updated curriculum aligns with recommendations from the American Board of Radiology Physics Study Guide Working Group. New technology has been integrated into the curriculum. The updated curriculum provides a framework to appropriately cover the educational topics for radiation oncology residents in preparation for their subsequent career development.

Comprehensive peripheral blood immunoprofiling reveals five immunotypes with immunotherapy response characteristics in patients with cancer.

The lack of comprehensive diagnostics and consensus analytical models for evaluating the status of a patient's immune system has hindered a wider adoption of immunoprofiling for treatment monitoring and response prediction in cancer patients. To address this unmet need, we developed an immunoprofiling platform that uses multiparameter flow cytometry to characterize immune cell heterogeneity in the peripheral blood of healthy donors and patients with advanced cancers. Using unsupervised clustering, we identified five immunotypes with unique distributions of different cell types and gene expression profiles. An independent analysis of 17,800 open-source transcriptomes with the same approach corroborated these findings. Continuous immunotype-based signature scores were developed to correlate systemic immunity with patient responses to different cancer treatments, including immunotherapy, prognostically and predictively. Our approach and findings illustrate the potential utility of a simple blood test as a flexible tool for stratifying cancer patients into therapy response groups based on systemic immunoprofiling.

Dosimetric perturbation from cloth and paper gowns for total skin electron irradiation.

Traditionally, total skin electron patients remove all clothing for treatment. It is generally assumed that this is best for the treatment of superficial skin lesions out of concern clothing may significantly perturb dose. We investigate the dosimetric effect of patient gowns and determine the necessity of treating patients naked. Using GAFCHROMIC EBT2 film, dose to a cylindrical phantom was measured with cloth, paper, and tri-layer cloth gowns, compared to no covering. A 6 MeV electron beam with spoiler accessory was used at ~ 4 meters source-to-skin distance. The gantry was angled at 248° and 292°. The phantom was rotated at -60°, 0°, and 60° relative to the beam's central axis, simulating the Stanford technique. This was also repeated for films sandwiched between the phantom's discs. Using a Markus chamber, the effect of air gaps of 0 to 5 cm in cloth and paper gowns was measured. The water equivalent attenuation of the gowns was determined through transmission studies. Compared to no covering, films placed on the phantom surface revealed an average increase of 0.8% in dose for cloth, 1.8% for tri-layered cloth, and 0.7% for paper. Films sandwiched within the phantom showed only slight shift of the percent depth-dose curves. Markus chamber readings revealed 1.4% for tri-layered cloth, and < 0.2% for single layer cloth or paper. Air gaps appeared to have a minimal effect. Transmission measurements found that one layer of cloth is equal to 0.2mm of solid water. Cloth and paper gowns appear to slightly increase the dose to the skin, but will not introduce any significant dose perturbation (<1%). Gowns having folds and extra layers will have a small additional perturbation (<2%). To minimize perturbation, one should smooth out any folds or remove any pockets that form extra layers on the gown.

Potential increase in biological effectiveness from field timing optimization for stereotactic body radiation therapy.

PURPOSE: Stereotactic body radiation therapy (SBRT) is a radiotherapy technique which uses high dose fractions with multiple coplanar and noncoplanar beams. Due to the large fractional doses, treatments are typically protracted and there are more fields than in conventional radiation treatment schemes. The effect of temporal optimization on the biological effectiveness of SBRT is not well established. METHODS: In a cohort of actual SBRT patient treatments, the Lea-Catcheside protraction factor (G-value) was used to determine the optimal (Δ) and the least favorable (V) field. An actual field timing delivered in the clinic was included (C) for comparison. The lethal potential lethal (LPL) model was used to quantify the difference in survival fractions. Published data from three cell lines for non-small cell lung cancers: H460, H660, and H157 were used to acquire the parameters needed by the LPL model. The results are expressed as the ratios (V:Δ)(N) and (C:Δ)(N), where N is the number fractions in the SBRT protocols and Δ, V, and C are the survival fractions calculated from the corresponding temporal patterns. RESULTS: The results indicate that variability in the dose rate between fields does impact the optimization results. This dependence on dose rate, however, is small compared to the impact from the variability in doses between fields. The optimized field arrangements resembled previous studies, that maximization of cell kill is achieved by orienting the fields in a Δ shape sequence, where the fields with greatest dose are positioned in the center. Minimization of cell kill was achieved with a V-shaped orientation. Smallest dose fields were positioned centrally, and higher dose fields were placed in the beginning and end of the fraction. The survival fraction ratios calculated using the LPL demonstrated that regardless of the cell type the Δ shape had lower cell survival fractions compared to both the clinical example (C) and the V arrangement. For H460, with T(1/2) = 0.25 h, an average ratio of (C:Δ)(5)=13.9, suggesting the Δ pattern is approximately 14 times more effective than the clinical plan, after 5 fractions. CONCLUSIONS: Rearranging field timing for a SBRT treatment so that maximal dose is deposited in the central fields of treatment may optimize cell kill and potentially affect overall treatment outcome.

A dosimetric evaluation of VMAT for the treatment of non-small cell lung cancer.

The purpose of this study was to demonstrate the dosimetric potential of volumetric-modulated arc therapy (VMAT) for the treatment of patients with medically inoperable stage I/II non-small cell lung cancer (NSCLC) with stereotactic body radiation therapy (SBRT). Fourteen patients treated with 3D CRT with varying tumor locations, tumor sizes, and dose fractionation schemes were chosen for study. The prescription doses were 48 Gy in 4 fractions, 52.5 Gy in 5 fractions, 57.5 Gy in 5 fractions, and 60 Gy in 3 fractions for 2, 5, 1, and 6 patients, respectively. VMAT treatment plans with a mix of two to three full and partial noncoplanar arcs with 5°-25° separations were retrospectively generated using Eclipse version 10.0. The 3D CRT and VMAT plans were then evaluated by comparing their target dose, critical structure dose, high dose spillage, and low dose spillage as defined according to RTOG 0813 and RTOG 0236 protocols. In the most dosimetrically improved case, VMAT was able to decrease the dose from 17.35 Gy to 1.54 Gy to the heart. The D(2cm) decreased in 11 of 14 cases when using VMAT. The three that worsened were still within the acceptance criteria. Of the 14 3D CRT plans, seven had a D(2cm) minor deviation, while only one of the 14 VMAT plans had a D(2cm) minor deviation. The R(50%) improved in 13 of the 14 VMAT cases. The one case that worsened was still within the acceptance criteria of the RTOG protocol. Of the 14 3D CRT plans, seven had an R(50%) deviation. Only one of the 14 VMAT plans had an R(50%) deviation, but it was still improved compared to the 3D CRT plan. In this cohort of patients, no evident dosimetric compromises resulted from planning SBRT treatments with VMAT relative to the 3D CRT treatment plans actually used in their treatment.

Mindful Parenting Mediated Between Mothers' Perceived Stress During COVID-19 and Child Adjustment.

Objectives: Maternal stress is associated with a myriad of maladjusted outcomes among children. To identify the role of mindful parenting between mothers' stress and child adjustment during the COVID-19 pandemic, this study tested competing hypotheses with mothers' mindful parenting as a mediator versus a moderator. Methods: A total of 172 Chinese mothers of preschool-aged children participated in this study. Participants completed a self-report measure of stress during COVID-19 and mindful parenting, as well as a mother-report measure of children's prosocial behavior, internalizing problems, and externalizing problems. Structural equation models were conducted to examine the mediation versus moderation effects of mindful parenting between mothers' stress during COVID-19 and child adjustment, after controlling for family income, children's age, sex, and adjustment at baseline. Results: Findings indicated that mindful parenting mediated the link between mothers' stress during COVID-19 and child adjustment, including internalizing problems, externalizing problems, and prosocial behavior. A test of competing hypothesis showed that mindful parenting did not moderate between mothers' stress during COVID-19 and child adjustment. Conclusions: This study revealed the mediating effects of mindful parenting between mothers' perceived stress during COVID-19 and child adjustment. The findings inform researchers and practitioners about mindful parenting as a potential mechanism between maternal stress and child adjustment during the pandemic.

Regulation of Peripheral Inflammation by a Non-Viable, Non-Colonizing Strain of Commensal Bacteria.

The gastrointestinal tract represents one of the largest body surfaces that is exposed to the outside world. It is the only mucosal surface that is required to simultaneously recognize and defend against pathogens, while allowing nutrients containing foreign antigens to be tolerated and absorbed. It differentiates between these foreign substances through a complex system of pattern recognition receptors expressed on the surface of the intestinal epithelial cells as well as the underlying immune cells. These immune cells actively sample and evaluate microbes and other particles that pass through the lumen of the gut. This local sensing system is part of a broader distributed signaling system that is connected to the rest of the body through the enteric nervous system, the immune system, and the metabolic system. While local tissue homeostasis is maintained by commensal bacteria that colonize the gut, colonization itself may not be required for the activation of distributed signaling networks that can result in modulation of peripheral inflammation. Herein, we describe the ability of a gut-restricted strain of commensal bacteria to drive systemic anti-inflammatory effects in a manner that does not rely upon its ability to colonize the gastrointestinal tract or alter the mucosal microbiome. Orally administered EDP1867, a gamma-irradiated strain of Veillonella parvula, rapidly transits through the murine gut without colonization or alteration of the background microbiome flora. In murine models of inflammatory disease including delayed-type hypersensitivity (DTH), atopic dermatitis, psoriasis, and experimental autoimmune encephalomyelitis (EAE), treatment with EDP1867 resulted in significant reduction in inflammation and immunopathology. Ex vivo cytokine analyses revealed that EDP1867 treatment diminished production of pro-inflammatory cytokines involved in inflammatory cascades. Furthermore, blockade of lymphocyte migration to the gut-associated lymphoid tissues impaired the ability of EDP1867 to resolve peripheral inflammation, supporting the hypothesis that circulating immune cells are responsible for promulgating the signals from the gut to peripheral tissues. Finally, we show that adoptively transferred T cells from EDP1867-treated mice inhibit inflammation induced in recipient mice. These results demonstrate that an orally-delivered, non-viable strain of commensal bacteria can mediate potent anti-inflammatory effects in peripheral tissues through transient occupancy of the gastrointestinal tract, and support the development of non-living bacterial strains for therapeutic applications.