Overcoming radioresistance of breast cancer cells with MAP4K4 inhibitors.

Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) has recently emerged as a promising therapeutic target in cancer. In this study, we explored the biological function of MAP4K4 in radioresistant breast cancer cells using two MAP4K4 inhibitors, namely PF06260933 and GNE-495. Radioresistant SR and MR cells were established by exposing SK-BR-3 and MCF-7 breast cancer cells to 48-70 Gy of radiation delivered at 4-5 Gy twice a week over 10 months. Surprisingly, although radioresistant cells were derived from two different subtypes of breast cancer cell lines, MAP4K4 was significantly elevated regardless of subtype. Inhibition of MAP4K4 with PF06260933 or GNE-495 selectively targeted radioresistant cells and improved the response to irradiation. Furthermore, MAP4K4 inhibitors induced apoptosis through the accumulation of DNA damage by inhibiting DNA repair systems in radioresistant cells. Notably, Inhibition of MAP4K4 suppressed the expressions of ACSL4, suggesting that MAP4K4 functioned as an upstream effector of ACSL4. This study is the first to report that MAP4K4 plays a crucial role in mediating the radioresistance of breast cancer by acting upstream of ACSL4 to enhance DNA damage response and inhibit apoptosis. We hope that our findings provide a basis for the development of new drugs targeting MAP4K4 to overcome radioresistance.

Toward Digital Twin Development for Implant Placement Planning Using a Parametric Reduced-Order Model.

Real-time stress distribution data for implants and cortical bones can aid in determining appropriate implant placement plans and improving the post-placement success rate. This study aims to achieve these goals via a parametric reduced-order model (ROM) method based on stress distribution data obtained using finite element analysis. For the first time, the finite element analysis cases for six design variables related to implant placement were determined simultaneously via the design of experiments and a sensitivity analysis. The differences between the minimum and maximum stresses obtained for the six design variables confirm that the order of their influence is: Young's modulus of the cancellous bone > implant thickness > front-rear angle > left-right angle > implant length. Subsequently, a one-dimensional (1-D) CAE solver was created using the ROM with the highest coefficient of determination and prognosis accuracy. The proposed 1-D CAE solver was loaded into the Ondemand3D program and used to implement a digital twin that can aid with dentists' decision making by combining various tooth image data to evaluate and visualize the adequacy of the placement plan in real time. Because the proposed ROM method does not rely entirely on the doctor's judgment, it ensures objectivity.

Stress induces behavioral abnormalities by increasing expression of phagocytic receptor MERTK in astrocytes to promote synapse phagocytosis.

Childhood neglect and/or abuse can induce mental health conditions with unknown mechanisms. Here, we identified stress hormones as strong inducers of astrocyte-mediated synapse phagocytosis. Using in vitro, in vivo, and human brain organoid experiments, we showed that stress hormones increased the expression of the Mertk phagocytic receptor in astrocytes through glucocorticoid receptor (GR). In post-natal mice, exposure to early social deprivation (ESD) specifically activated the GR-MERTK pathway in astrocytes, but not in microglia. The excitatory post-synaptic density in cortical regions was reduced in ESD mice, and there was an increase in the astrocytic engulfment of these synapses. The loss of excitatory synapses, abnormal neuronal network activities, and behavioral abnormalities in ESD mice were largely prevented by ablating GR or MERTK in astrocytes. Our work reveals the critical roles of astrocytic GR-MERTK activation in evoking stress-induced abnormal behaviors in mice, suggesting GR-MERTK signaling as a therapeutic target for stress-induced mental health conditions.

Schizophrenia-associated Mitotic Arrest Deficient-1 (MAD1) regulates the polarity of migrating neurons in the developing neocortex.

Although large-scale genome-wide association studies (GWAS) have identified an association between MAD1L1 (Mitotic Arrest Deficient-1 Like 1) and the pathology of schizophrenia, the molecular mechanisms underlying this association remain unclear. In the present study, we aimed to address these mechanisms by examining the role of MAD1 (the gene product of MAD1L1) in key neurodevelopmental processes in mice and human organoids. Our findings indicated that MAD1 is highly expressed during active cortical development and that MAD1 deficiency leads to impairments in neuronal migration and neurite outgrowth. We also observed that MAD1 is localized to the Golgi apparatus and regulates vesicular trafficking from the Golgi apparatus to the plasma membrane, which is required for the growth and polarity of migrating neurons. In this process, MAD1 physically interacts and collaborates with the kinesin-like protein KIFC3 (kinesin family member C3) to regulate the morphology of the Golgi apparatus and neuronal polarity, thereby ensuring proper neuronal migration and differentiation. Consequently, our findings indicate that MAD1 is an essential regulator of neuronal development and that alterations in MAD1 may underlie schizophrenia pathobiology.

Physicochemical Properties of Yanggaeng with Added Tempeh Powder.

In this study, we investigated the physicochemical and antioxidative properties of the traditional Korean confectionery, Yanggaeng, when various amounts of tempeh powder (TP) were added. We replaced a portion of the white bean paste in Yanggaeng with TP at percentages of 0% (CON), 2% (TP2), 4% (TP4), and 6% (TP6) by total weight. The proximate composition results showed that TP6 exhibited the highest crude ash and crude protein contents, but its moisture content and carbohydrate content were the lowest compared to the CON. Tempeh addition altered the colorimetric properties by increasing the L* value, b* value, and browning index; however, tempeh addition did not alter the a* value. The results also showed that tempeh addition gradually decreased the pH of Yanggaeng. The Brix value was the highest in TP2; in TP4 and TP6, the Brix value gradually decreased, and these formulations exhibited lower Brix values than the CON. Furthermore, tempeh addition gradually induced antioxidative capacities, as evidenced by 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical scavenging activities. The results of this study demonstrate that the addition of tempeh to Yanggaeng alters its physicochemical properties and antioxidative capacity.

Serum and glucocorticoid-regulated kinase 1: Structure, biological functions, and its inhibitors.

Serum and glucocorticoid-regulated kinase 1 (SGK1) is a serine/threonine kinase belonging to the protein kinase A, G, and C (AGC) family. Upon initiation of the phosphoinositide 3-kinase (PI3K) signaling pathway, mammalian target of rapamycin complex 2 (mTORC2) and phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylate the hydrophobic motif and kinase domain of SGK1, respectively, inducing SGK1 activation. SGK1 modulates essential cellular processes such as proliferation, survival, and apoptosis. Hence, dysregulated SGK1 expression can result in multiple diseases, including hypertension, cancer, autoimmunity, and neurodegenerative disorders. This review provides a current understanding of SGK1, particularly in sodium transport, cancer progression, and autoimmunity. In addition, we summarize the developmental status of SGK1 inhibitors, their structures, and respective potencies evaluated in pre-clinical experimental settings. Collectively, this review highlights the significance of SGK1 and proposes SGK1 inhibitors as potential drugs for treatment of clinically relevant diseases.

Quality of life and caregiver burden in pediatric glaucoma: A systematic review.

Pediatric conditions can lead to significant caregiver burden and poor quality of life (QoL). This systematic review describes research relating to caregiver burden and QoL of caregivers of pediatric glaucoma patients. A systematic database search of Embase, Medline, PsycINFO, CINAHL, Web of Science, and the three journals within the Association for Research in Vision and Ophthalmology (ARVO) was conducted in October 2021. Publications underwent abstract and full-text screening and were included if they reported pediatric caregivers' QoL using quantitative or qualitative methods. Review articles, publications not in English, and articles focusing on adult glaucoma patients were excluded. Studies then underwent risk of bias assessment and data extraction. Of the 105 publications identified, 8 publications with 667 participants were included in the review. Studies indicated significantly higher burden and poor QoL in caregivers. Female sex, lower education level, lower income, and working status of caregivers were associated with poorer QoL and greater burden. Additionally, more severe and longer duration of the child's disease negatively impacted these measures of caregiver wellbeing. Additionally, studies found significant improvement in caregiver QoL after patients underwent surgery with combined trabeculotomy-trabeculectomy. In conclusion, few studies have investigated the impact of pediatric glaucoma on caregivers. This review of the existing studies found poor QoL and high levels of caregiver burden within this population. Given the lifelong nature of pediatric glaucoma, there is a need for further longitudinal research focusing on the caregivers of these pediatric patients. Long-term follow-up would allow for a greater understanding of how caregiver QoL changes over the course of the disease.

Enhancement of Thermoplasmonic Neural Modulation Using a Gold Nanorod-Immobilized Polydopamine Film.

Photothermal neural activity inhibition has emerged as a minimally invasive neuromodulation technology with submillimeter precision. One of the techniques involves the utilization of plasmonic gold nanoparticles (AuNPs) to modulate neural activity by photothermal effects ("thermoplasmonics"). A surface modification technique is often required to integrate AuNPs onto the neural interface. Here, polydopamine (pDA), a multifunctional adhesive polymer with a wide light absorption spectrum, is introduced both as a primer layer for the immobilization of gold nanorods (GNRs) on the neural interface and as an additional photothermal agent by absorbing near-infrared red (NIR) lights for more efficient photothermal effects. First, the optical and photothermal properties of pDA as well as the characteristics of GNRs attached onto the pDA film are investigated for the optimized photothermal neural interface. Due to the covalent bonding between GNR surfaces and pDA, GNRs immobilized on pDA showed strong attachment onto the surface, yielding a more stable photothermal platform. Lastly, when photothermal neural stimulation was applied to the primary rat hippocampal neurons, the substrate with GNRs immobilized on the pDA film allowed more laser power-efficient photothermal neuromodulation as well as photothermal cell death. This study suggests the feasibility of using pDA as a surface modification material for developing a photothermal platform for the inhibition of neural activities.

Engineering Brain Organoids: Toward Mature Neural Circuitry with an Intact Cytoarchitecture.

The emergence of brain organoids as a model system has been a tremendously exciting development in the field of neuroscience. Brain organoids are a gateway to exploring the intricacies of human-specific neurogenesis that have so far eluded the neuroscience community. Regardless, current culture methods have a long way to go in terms of accuracy and reproducibility. To perfectly mimic the human brain, we need to recapitulate the complex in vivo context of the human fetal brain and achieve mature neural circuitry with an intact cytoarchitecture. In this review, we explore the major challenges facing the current brain organoid systems, potential technical breakthroughs to advance brain organoid techniques up to levels similar to an in vivo human developing brain, and the future prospects of this technology.

Evaluation of Radiotherapy-Induced Systemic Antitumor Effects in Mice Bearing 4T1 Mouse Breast Cancer Cells.

Background: Recently, several clinical studies have reported that combination treatments of radiation therapy (RT) and immunotherapy in patients with multiple lesions can improve tumor regression at a distance from the irradiated site, known as the abscopal effect. However, when RT and immunotherapy are concurrently applied, it is hard to distinguish the pure systemic effects of RT from those of the immunotherapy drug. In this preclinical study, the authors investigated the systemic antitumor effects of RT alone according to fraction dose size and splitting schedules. Materials and Methods: 4T1 mouse breast cancer cells were implanted into the right and left sides of mammary gland fat pads of BALB/c mice, followed by irradiation with 6 Gy × 3, 8 Gy × 2, and 13 Gy × 1 fractions when the right-side tumors were palpable. Results: The different irradiation schedules produced similar antitumor effects in irradiated right-side tumors and unirradiated left-side tumors. However, 8 Gy × 2 and 13 Gy × 1 fractions exhibited better antimetastatic potential than that from irradiation using 6 Gy × 3 fractions. Furthermore, 8 Gy × 2 and 13 Gy × 1 fractions produced higher expressions of HMGB1 and lower expressions of the proinflammatory cytokines, IFN-γ, TNF-α, IL-6, and IL-1ß, from the irradiated tumor tissues. Conclusions: These findings suggest that 8 Gy × 2 and 13 Gy × 1 fractions can provide better systemic antitumor effects than 6 Gy × 3 fractions. The authors hope these results provide clues to optimize RT dose regimens to make the abscopal effect clinically more relevant in future combination treatments.

insomniac links the development and function of a sleep-regulatory circuit.

Although many genes are known to influence sleep, when and how they impact sleep-regulatory circuits remain ill-defined. Here, we show that insomniac (inc), a conserved adaptor for the autism-associated Cul3 ubiquitin ligase, acts in a restricted period of neuronal development to impact sleep in adult Drosophila. The loss of inc causes structural and functional alterations within the mushroom body (MB), a center for sensory integration, associative learning, and sleep regulation. In inc mutants, MB neurons are produced in excess, develop anatomical defects that impede circuit assembly, and are unable to promote sleep when activated in adulthood. Our findings link neurogenesis and postmitotic development of sleep-regulatory neurons to their adult function and suggest that developmental perturbations of circuits that couple sensory inputs and sleep may underlie sleep dysfunction in neurodevelopmental disorders.

Effective Organs-at-Risk Dose Sparing in Volumetric Modulated Arc Therapy Using a Half-Beam Technique in Whole Pelvic Irradiation.

BACKGROUND: Although there are some controversies regarding whole pelvic radiation therapy (WPRT) due to its gastrointestinal and hematologic toxicities, it is considered for patients with gynecological, rectal, and prostate cancer. To effectively spare organs-at-risk (OAR) doses using multi-leaf collimator (MLC)'s optimal segments, potential dosimetric benefits in volumetric modulated arc therapy (VMAT) using a half-beam technique (HF) were investigated for WPRT. METHODS: While the size of a fully opened field (FF) was decided to entirely include a planning target volume in all beam's eye view across arc angles, the HF was designed to use half the FF from the isocenter for dose optimization. The left or the right half of the FF was alternatively opened in VMAT-HF using a pair of arcs rotating clockwise and counterclockwise. Dosimetric benefits of VMAT-HF, presented with dose conformity, homogeneity, and dose-volume parameters in terms of modulation complex score, were compared to VMAT optimized using the FF (VMAT-FF). Consequent normal tissue complication probability (NTCP) by reducing the irradiated volumes was evaluated as well as dose-volume parameters with statistical analysis for OAR. Moreover, beam-on time and MLC position precision were analyzed with log files to assess plan deliverability and clinical applicability of VMAT-HF as compared to VMAT-FF. RESULTS: While VMAT-HF used 60%-70% less intensity modulation complexity than VMAT-FF, it showed superior dose conformity. The small intestine and colon in VMAT-HF showed a noticeable reduction in the irradiated volumes of up to 35% and 15%, respectively, at an intermediate dose of 20-45 Gy. The small intestine showed statistically significant dose sparing at the volumes that received a dose from 15 to 45 Gy. Such a dose reduction for the small intestine and colon in VMAT-HF presented a significant NTCP reduction from that in VMAT-FF. Without sacrificing the beam delivery efficiency, VMAT-HF achieved effective OAR dose reduction in dose-volume histograms. CONCLUSIONS: VMAT-HF led to deliver conformal doses with effective gastrointestinal-OAR dose sparing despite using less modulation complexity. The dose of VMAT-HF was delivered with the same beam-on time with VMAT-FF but precise MLC leaf motions. The VMAT-HF potentially can play a valuable role in reducing OAR toxicities associated with WPRT.

Acyl-CoA synthetase-4 mediates radioresistance of breast cancer cells by regulating FOXM1.

The development of radioresistance during radiotherapy is a major cause of tumor recurrence and metastasis. To provide new insights of the mechanisms underlying radioresistance, we established radioresistant cell lines derived from two different subtypes of breast cancer cells, HER2-positive SK-BR-3 and ER-positive MCF-7 breast cancer cells, by exposing cells to 48 ~ 70 Gy of radiation delivered at 4-5 Gy twice weekly over 9 ~ 10 months. The established radioresistant SK-BR-3 (SR) and MCF-7 (MR) cells were resistant not only to a single dose of radiation (2 Gy or 4 Gy) but also to fractionated radiation delivered at 2 Gy/day for 5 days. Furthermore, these cells exhibited tumor-initiating potential in vivo and high CD24-/CD44 + ratio. To identify novel therapeutic molecular targets, we analyzed differentially expressed genes in both radioresistant cell lines and found that the expression of ACSL4 was significantly elevated in both cell lines. Targeting ACSL4 improved response to irradiation and inhibited migration activities. Furthermore, inhibition of ACLS4 using ASCL4 siRNA or triacsin C suppressed FOXM1 expression, whereas inhibition of FOXM1 using thiostrepton did not affect ACSL4 expression. Targeting the ACSL4-FOXM1 signaling axis by inhibiting ASCL4 or FOXM1 overcame the radioresistance by suppressing DNA damage responses and inducing apoptosis. This is the first study to report that ACSL4 plays a crucial role in mediating the radioresistance of breast cancer by regulating FOXM1. We propose the ACSL4-FOXM1 signaling axis be considered a novel therapeutic target in radioresistant breast cancer and suggest treatment strategies targeting this signaling axis might overcome breast cancer radioresistance.

Aggravation of Hemorrhoids in Patients With Cervical Cancer Undergoing Radiotherapy: A Nationwide Population-based Study.

BACKGROUND/AIM: Anal canal toxicity tends to be ignored in pelvic radiotherapy (RT). However, patients with hemorrhoids can be troubled by lower radiation dose. We tried to determine whether a correlation exists between hemorrhoids and anal symptoms in patients with cervical cancer undergoing RT. PATIENTS AND METHODS: The insurance claim data of patients who underwent definitive treatment for cervical cancer from 2015 to 2019 were analyzed. Adverse events including bleeding, proctitis, and hemorrhoids, were documented for 1 year after treatment completion. Odds ratios (ORs) were estimated by unconditional Poisson regression and adjusted for age, treatments, chemotherapy, and comorbidities. RESULTS: Details of 67,114 insured cervical cancer patients treated between 2015 and 2019 were obtained. Among them, 5,919 patients with follow-up data for at least one year, treated with curative intent, were analyzed. The OR of the definitive radiotherapy group (DRT group) for anal bleeding was 10.57 higher than that of the operation alone group (surgical group) (p<0.01). Newly developed hemorrhoids gradually increased in the surgical group (3.17%), the postoperative radiotherapy group (5.38%), and the DRT group (7.58%). The OR of the DRT group for newly developed hemorrhoids was 2.38 higher than that of the surgical group (p<0.01), and ORs increased to 1.99 and 1.61 in patients that received chemotherapy and patients with diabetes, respectively (p<0.01). CONCLUSION: Pelvic RT increased anal bleeding and symptomatic hemorrhoids. In particular, chemotherapy and diabetes also increased the risk. If patients with hemorrhoids receive pelvic RT, attention is required to prevent hemorrhoid aggravation.

Chaga mushroom extract induces autophagy via the AMPK-mTOR signaling pathway in breast cancer cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Chaga mushrooms (Inonotus obliquus) are commonly used in traditional treatments in Eastern Europe and Asia due to their diverse pharmacological effects, including anti-tumor and immunologic effects. Thus, many cancer patients take Chaga mushrooms as a complementary medicine, even during chemotherapy or radiotherapy. However, few studies have investigated the effects or molecular targets of Chaga mushrooms in breast cancer. AIM OF THE STUDY: Herein, we examined the anticancer effects of Chaga mushrooms in different types of breast cancer cell lines, and explored the underlying molecular mechanism to better understand their effects and benefits. MATERIALS AND METHODS: Chaga mushroom extract (CME) was prepared by extracting Chaga mushrooms with 70% ethanol. The cytotoxic effects of CME were assessed by MTT assay and protein expressions were evaluated by western blotting. To evaluate in vivo anti-tumor effects of CME, CME (2 g/kg) was orally administered to 4T1 tumor-bearing BALB/c mice every other day over 30 days (15 administrations), and tumor sizes were measured. Silica gel column chromatography was used to fractionate CME, and major constituents responsible for cytotoxic effects of CME were identified by 1H/13C-NMR and LC-MS. RESULTS: CME inhibited the proliferation of 4T1 mouse breast cancer cells in a dose and time-dependent manner. The expression of LC3 and phosphorylation of AMPK were increased by CME, while the phosphorylation of mTOR, S6, and S6K1 were suppressed, suggesting that CME induced autophagy by activating AMPK and inhibiting mTOR signaling pathways. Consistent with its observed cytotoxic effect in vitro, CME effectively suppressed tumor growth in 4T1 tumor-bearing BALB/c mice. In addition, inotodiol and trametenolic acid were identified as the major constituents responsible for the cytotoxic effects of CME on breast cancer cells. Moreover, inotodiol and trametenolic acid-enriched fractions both exhibited cytotoxic effects regardless of breast cancer cell subtypes and did not interfere with the cytotoxic effects of conventional drugs. CONCLUSIONS: Taken together, Chaga mushroom extract induced autophagy by activating AMPK and inhibiting the mTOR signaling pathway. Our data suggest Chaga mushrooms may be a beneficial complementary medicine for breast cancer patients.

Repeat Selective Laser Trabeculoplasty for Glaucoma Patients: A Systematic Review and Meta-analysis.

AIM AND OBJECTIVE: To evaluate repeat selective laser trabeculoplasty (SLT) for treating primary open-angle glaucoma (POAG). MATERIALS AND METHODS: PubMed, CINAHL, and EMBASE were systematically searched along with grey literature. All English articles that measured intraocular pressure (IOP) before and after repeat SLT on adult patients with POAG were included. Studies were not filtered by location or publication date. Covidence was used to screen imported articles. Risk of bias assessment and data extraction was performed after screening. Meta-analysis was performed using STATA 16.0. Fixed-effect or random-effects models were developed depending on the presence of heterogeneity. RESULTS: Database and grey literature search identified 512 unique studies. After duplicate removal and screening, 12 articles were included and data from included studies were synthesized. Nine articles were included in the meta-analysis. Three studies were prospective observational studies, and nine studies were retrospective chart reviews. Due to the presence of heterogeneity, a random-effects model has been utilized that suggested significant IOP reduction (IOPR) by repeat SLT at 24 months follow-up. CONCLUSION: Based on our results, repeat SLT could be an effective procedure in reducing IOP for patients with glaucoma for up to 24 months. Efficacy of third, fourth, or further SLT remains to be verified. More data from long-term, high-quality randomized-controlled trials (RCTs) are required to make conclusions. CLINICAL SIGNIFICANCE: Repeat SLT may be an effective treatment for lowering IOP with minimal complications or safety issues. This may allow the use of SLT as a primary treatment for POGA, allowing the discontinuation of medications or eye drops and lead to additional benefits. HOW TO CITE THIS ARTICLE: Jang HJ, Yu B, Hodge W, et al. Repeat Selective Laser Trabeculoplasty for Glaucoma Patients: A Systematic Review and Meta-analysis. J Curr Glaucoma Pract 2021;15(3):117-124.

Assessment of portal image resolution improvement using an external aluminum target and polystyrene electron filter.

BACKGROUND: In this study, an external 8 mm thick aluminum target was installed on the upper accessory tray mount of a medical linear accelerator head. The purpose of this study was to determine the effects of the external aluminum target beam (Al-target beam) on the portal image quality by analyzing the spatial and contrast resolutions. In addition, the image resolutions with the Al-target beams were compared with those of conventional 6 megavoltage (MV) images. METHODS: The optimized Al-target beam was calculated using Monte Carlo simulations. To validate the simulations, the percentage depth dose and lateral profiles were measured and compared with the modeled dose distributions. A PTW resolution phantom was used for imaging to assess the image resolution. The spatial resolution was quantified by determining the modulation transfer function. The contrast resolution was determined by a fine contrast difference between the 27 measurement areas. The spatial and contrast resolutions were compared with the those of conventional portal images. RESULTS: The measured and calculated percentage depth dose of the Al-target beam were consistent within 1.6%. The correspondence of measured and modelled profiles was evaluated by gamma analysis (3%, 3 mm) and all gamma values inside the field were less than one. The critical spatial frequencies (f50) of the images obtained with the Al-target beam and conventional imaging beam were 0.745 lp/mm and 0.451 lp/mm, respectively. The limiting spatial frequencies (f10) for the Al-target beam image and the conventional portal image were 2.39 lp/mm and 1.82 lp/mm, respectively. The Al-target beam resolved the smaller and lower contrast objects better than that of the MV photon beam. CONCLUSION: The Al-target beams generated by the simple target installation method provided better spatial and contrast resolutions than those of the conventional 6 MV imaging beam.

Characterization and comparative expression analysis of CUL1 genes in rice.

Cullin-RING E3 ubiquitin ligase (CRL) complex is known as the largest family of E3 ligases. The most widely characterized CRL, SCF complex (CRL1), utilizes CUL1 as a scaffold protein to assemble the complex components. To better understand CRL1-mediated cellular processes in rice, three CUL1 genes (OsCUL1s) were isolated in Oryza sativa. Although all OsCUL1 proteins exhibited high levels of amino acid similarities with each other, OsCUL1-3 had a somewhat distinct structure from OsCUL1-1 and OsCUL1-2. Basal expression levels of OsCUL1-3 were much lower than those of OsCUL1-1 and OsCUL1-2 in all selected samples, showing that OsCUL1-1 and OsCUL1-2 play predominant roles relative to OsCUL1-3 in rice. OsCUL1-1 and OsCUL1-2 genes were commonly upregulated in dry seeds and by ABA and salt/drought stresses, implying their involvement in ABA-mediated processes. These genes also showed similar expression patterns in response to various hormones and abiotic stresses, alluding to their functional redundancy. Expression of the OsCUL1-3 gene was also induced in dry seeds and by ABA-related salt and drought stresses, implying their participation in ABA responses. However, its expression pattern in response to hormones and abiotic stresses was somehow different from those of the OsCUL1-1 and OsCUL1-2 genes. Taken together, these findings suggest that the biological role and function of OsCUL1-3 may be distinct from those of OsCUL1-1 and OsCUL1-2. The results of expression analysis of OsCUL1 genes in this study will serve as a useful platform to better understand overlapping and distinct roles of OsCUL1 proteins and CRL1-mediated cellular processes in rice plants.

Investigation of the use of external aluminium targets for portal imaging in a medical accelerator using Geant4 Monte Carlo simulation.

OBJECTIVE: To install a low-Z target on the wedge tray mount of a medical linear accelerator to create a new image beam and to confirm image contrast enhancement. METHODS: Experimental low-energy photon beams were produced with the linac running in the 6 MeV electron mode and with a low-Z target installed on the wedge tray mount [denoted 6 MeV (low-Z target)]. Geant4 Monte Carlo simulation was performed to analyse the energy spectrum and image contrast of a 6 MeV (low-Z target) beam. This study modelled the 6 MeV (low-Z target) beam and the 6 MV (megavoltage) radiotherapy photon beam and verified model validity by measurement. In addition, a contrast phantom was modelled to quantitatively compare the image contrasts of the 6 MeV (low-Z target) beam and the 6 MV radiotherapy photon beam. A low-Z target was fabricated to generate low-energy photons (25-150 keV) from incident electrons, and a portal image of the Alderson RANDO phantom was acquired using a clinical linear accelerator for qualitative analysis. RESULTS: The measured and calculated percentage depth dose of the 6 MV photon and 6 MeV (Al) beams were consistent within 1.5 and 1.6%, respectively, and calculated lateral profiles of the 6 MV photon beam and the 6 MeV (Al) beam were consistent with the measured results within 1.5 and 1.9%, respectively. Although low-energy photons (25-150 keV) of the 6 MV photon beam were only 0.3%, the Be, C, and Al low-Z targets, but not the Ti target, generated 34.4 to 38.5% low-energy photons. In 5 to 20 cm water phantoms, contrast of the 6 MeV (Al) beam was approximately 1.16 times greater than that of the 6 MV beam. The contrasts of 6 MeV (Al) and 6 MV photon beams in the 20 cm water phantom were ~34% lower than those in the 5 cm water phantom. 6 MeV (Al)/CR (computed radiography) images of the human body phantom were more vivid and detailed than 6 MV/EPID (electronic portal imaging device) and 6 MeV (Al)/EPID images. CONCLUSION: The experimental beam with a low-Z target, which was simply installed on the wedge tray mount of the radiotherapy linear accelerator, generated significantly more low-energy photons than the 6 MV radiotherapy photon beam, and provided better quality portal images. Advances in knowledge: This study shows that, unlike the existing low-Z beam studies, a low-Z target can be installed outside the head of a linear accelerator to improve portal image quality.

Comparison of Treatment Outcomes between Breast Conserving Surgery Followed by Radiotherapy and Mastectomy Alone in Patients with T1-2 Stage and 1-3 Axillary Lymph Nodes in the Era of Modern Adjuvant Systemic Treatments.

PURPOSE: The role of postmastectomy radiotherapy in the treatment of T1-2 primary tumor with 1-3 positive lymph nodes is controversial. We compared treatment outcomes between breast conserving surgery followed by radiotherapy (BCS+RT) and total mastectomy alone (TM) in the setting of modern adjuvant systemic treatments. METHODS: Patients with T1-2 primary breast cancer and 1-3 positive lymph nodes who were treated between 2001 and 2011 were divided into 2 groups based on the treatment approach: BCS+RT (n = 169) and TM (n = 117). All patients received adjuvant chemotherapy including taxanes. Adjuvant endocrine therapy was administered to patients with positive hormone receptors according to their menstrual status. RESULTS: During a median follow-up of 76.5 months, 21 patients (7.3%) experienced locoregional recurrence as the first event, including 7 patients (4.1%) in the BCS+RT group and 14 patients (12.0%) in the TM group. The 5-year cumulative incidence rate of locoregional recurrence was 2.5% for BCS+RT versus 9.5% for TM (p = 0.016). Competing risk regression analysis revealed that TM was associated with a relative risk for locoregional recurrence of 5.347 (p = 0.003). TM was also associated with a significantly lower 5-year disease-free survival rate compared with BCS+RT (hazard ratio, 2.024; 95% confidence interval, 1.090-3.759; p = 0.026). CONCLUSION: To improve treatment outcomes for TM even after modern systemic treatments, postmastectomy radiotherapy might be required for patients with T1-2 primary breast cancer and 1-3 positive lymph nodes.