IL-6 Inhibitory Compounds from the Aerial Parts of Piper attenuatum and Their Anticancer Activities on Ovarian Cancer Cell Lines.

Piper attenuatum Buch-Ham, a perennial woody vine belonging to the Piperaceae family, is traditionally used in Southeast Asia for treating various ailments such as malaria, headache, and hepatitis. This study described the isolation and identification of three new compounds, piperamides I-III (1-3), which belong to the maleimide-type alkaloid skeletons, along with fifteen known compounds (4-18) from the methanol extract of the aerial parts of P. attnuatum. Their chemical structures were elucidated using spectroscopic methods (UV, IR, ESI-Q-TOF-MS, and 1D/2D NMR). All the isolates were evaluated for their ability to inhibit IL-6 activity in the human embryonic kidney-Blue™ IL-6 cell line and their cytotoxic activity against ovarian cancer cell lines (SKOV3/SKOV3-TR) and chemotherapy-resistant variants (cisplatin-resistant A2780/paclitaxel-resistant SKOV3). The compounds 3, 4, 11, 12, 17, and 18 exhibited IL-6 inhibition comparable to that of the positive control bazedoxifene. Notably, compound 12 displayed the most potent anticancer effect against all the tested cancer cell lines. These findings highlight the importance of researching the diverse activities of both known and newly discovered natural products to fully unlock their potential therapeutic benefits.

Successful Long-Term Multimodality Management of Facial Lesions in Tuberous Sclerosis Complex in an Adult Patient.

Angiofibroma and shagreen patches are common cutaneous manifestations of tuberous sclerosis complex (TSC) and have significant physical and psychological repercussions for patients. Several treatments have been proposed to improve lesions; however, clear treatment guidelines have not yet been presented. Thus, we introduce a case of angiofibroma and shagreen patch improved by application of pulsed dye laser, ablative fractional CO2 laser, and topical rapamycin, and present clinical implications for the treatment of angiofibroma and shagreen patch in TSC.

A case of Joubert syndrome caused by novel compound heterozygous variants in the TMEM67 gene.

Joubert syndrome (JS) is a recessive disorder that is characterized by midbrain-hindbrain malformation and shows the "molar tooth sign" on magnetic resonance imaging. Mutations in 40 genes, including Abelson helper integration site 1 (AHI1), inositol polyphosphate-5-phosphatase (INPP5E), coiled-coil and c2 domain-containing protein 2A (CC2D2A), and ARL2-like protein 1 (ARL13B), can cause JS. Classic JS is a part of a group of diseases associated with JS, and its manifestations include various neurological signs such as skeletal abnormalities, ocular coloboma, renal disease, and hepatic fibrosis. Here, we present a proband with the molar tooth sign, ataxia, and developmental and psychomotor delays in a Dagestan family from Russia. Molecular genetic testing revealed two novel heterozygous variants, c.2924G>A (p.Arg975His) in exon 28 and c.1241C>G (p.Pro414Arg) in exon 12 of the transmembrane protein 67 (TMEM67) gene. These TMEM67 gene variants significantly affected the development of JS type 6. This case highlights the importance of whole exome sequencing for a proper clinical diagnosis of children with complex motor and psycho-language delays. This case also expands the clinical phenotype and genotype of TMEM67-associated diseases.

Metastatic cutaneous squamous cell carcinoma to the parotid: Adjuvant radiotherapy and treatment outcomes.

INTRODUCTION: Adjuvant radiotherapy is an established component in the management of metastatic cutaneous squamous cell carcinoma (SCC) involving the parotid gland. Radiotherapy technique, dose and volumes are seldom described sufficiently to allow close examination. We report our treatment outcomes and focus on treatment-related factors that affect outcomes in this cohort. METHODS: We performed a retrospective review of patients with metastatic cutaneous SCCs who underwent parotidectomy with or without ipsilateral neck dissection. All patients received adjuvant radiotherapy. Demographics, clinical data and treatment details were collected from an intuitional electronic database. Individual patient-level radiotherapy technique, volumes and doses were reviewed. RESULTS: Between July 2008 and July 2018, 60 patients met our inclusion criteria. Median follow-up duration was 32.7 months. The mean age was 66.4 years. The majority of patients (49 patients) received full neck irradiation. The 2-year and 5-year loco-regional failure-free survival was 87% (95% confidence interval (CI): 0.74-0.93) and 71% (95% CI: 0.52, 0.83), respectively. The 2-year and 5-year overall survival was 76% (95% CI: 0.62, 0.85) and 60% (95% CI: 0.45, 0.72), respectively. There were 15 cases of loco-regional failures, with 6 cases with dermal involvement. Lymphovascular invasion (LVI) was associated with higher loco-regional failure (hazard ratio: 8.43, 95% CI: 1.85-38.39, P = 0.005) and cancer-specific mortality (hazard ratio: 5.40, 95% CI: 1.40-20.87, P = 0.015). Treatment technique, intensity-modulated radiation therapy (IMRT) vs 3D conformal radiotherapy (3D CRT), bolus use, perineural invasion (PNI) and surgical margins were not significantly associated with loco-regional failure. CONCLUSION: We demonstrated high loco-regional control rates with routine use of comprehensive adjuvant radiotherapy. The presence of LVI was identified as a strong predictor for recurrence. Further analysis will help to define optimal radiation dose and techniques.

Chronic Alcohol Exposure Promotes Cancer Stemness and Glycolysis in Oral/Oropharyngeal Squamous Cell Carcinoma Cell Lines by Activating NFAT Signaling.

Alcohol consumption is associated with an increased risk of several cancers, including oral/oropharyngeal squamous cell carcinoma (OSCC). Alcohol also enhances the progression and aggressiveness of existing cancers; however, its underlying molecular mechanism remains elusive. Especially, the local carcinogenic effects of alcohol on OSCC in closest contact with ingestion of alcohol are poorly understood. We demonstrated that chronic ethanol exposure to OSCC increased cancer stem cell (CSC) populations and their stemness features, including self-renewal capacity, expression of stem cell markers, ALDH activity, and migration ability. The ethanol exposure also led to a significant increase in aerobic glycolysis. Moreover, increased aerobic glycolytic activity was required to support the stemness phenotype of ethanol-exposed OSCC, suggesting a molecular coupling between cancer stemness and metabolic reprogramming. We further demonstrated that chronic ethanol exposure activated NFAT (nuclear factor of activated T cells) signaling in OSCC. Functional studies revealed that pharmacological and genetic inhibition of NFAT suppressed CSC phenotype and aerobic glycolysis in ethanol-exposed OSCC. Collectively, chronic ethanol exposure promotes cancer stemness and aerobic glycolysis via activation of NFAT signaling. Our study provides a novel insight into the roles of cancer stemness and metabolic reprogramming in the molecular mechanism of alcohol-mediated carcinogenesis.

Dynamic thermal imaging for pigmented basal cell carcinoma and seborrheic keratosis.

BACKGROUND: Clinical differentiation between pigmented basal cell carcinoma (BCC) and seborrheic keratosis (SK) can sometimes be difficult. Noninvasive diagnostic technologies, such as thermal imaging, can be helpful in these situations. This study explored the use of dynamic thermal imaging (DTI), which records thermal images after the application of external thermal stimuli (heat or cold) for the differential diagnosis of pigmented BCC and SK. MATERIALS AND METHODS: Twenty-two patients with pigmented BCC and 15 patients with SK participated in this study. Dynamic thermal images of lesions (pigmented BCC or SK) and control sites (contralateral normal skin) were recorded after the heat and cold stimuli. Temperature changes in the region of interest (ROI) are plotted as a thermal response graph. After fitting an exponential equation to each thermal response graph, the rate constants were compared between groups (pigmented BCC versus control, SK versus control). RESULTS: The thermal response graphs revealed that the average temperature of pigmented BCC showed faster thermal recovery to baseline than the control site. There was a significant difference in the rate constants of the fitted exponential equations between the pigmented BCCs and the control sites (p<.001). However, we did not find a significantly different thermal recovery pattern between SK lesions and control sites. CONCLUSIONS: DTI can be used as a diagnostic tool for distinguishing pigmented BCC from SK by comparing thermal recovery patterns between target lesions (pigmented BCC or SK) and the control site.

A Systematic Review of Complex Polypharmacy in Bipolar Disorder: Prevalence, Clinical Features, Adherence, and Preliminary Recommendations for Practitioners.

Objective: Extensive combination pharmacotherapy regimens for bipolar disorder have gained increasing use in routine practice in ways that outpace data from evidence-based clinical trials. The present review examined the prevalence of complex pharmacotherapy regimens in bipolar disorder patients and sought to characterize factors that most influence polypharmacy prescribing patterns.Data Sources: The authors independently systematically searched the MEDLINE, PsycINFO, and Embase databases for English-language observational/naturalistic or randomized controlled polypharmacy trials, using the keywords bipolar and polypharmacy or bipolar and combination treatment and pharmacotherapy.Study Selection: From among 3,566 publications, 49 ultimately met study inclusion criteria.Data Extraction: Information was obtained regarding prevalence rates of extensive polypharmacy as well as clinical characteristics and naturalistic outcomes for patients with simple (≤ 2) or complex (≥ 3) regimens of psychotropic agents.Results: A weighted mean percentage of 32.7% of bipolar outpatients (4,535/13,863) taking ≥ 3 psychotropic medications was identified. Factors associated with complex polypharmacy use include female sex, White race, age > 50 years, history of psychosis, greater burden of depressive illness, subtherapeutic dosing, lower treatment adherence, more extensive psychiatric comorbidity, and a greater history of suicide attempts.Conclusions: Extensive or complex combination pharmacotherapy regimens are common in many patients with bipolar disorder and often reflect greater overall illness severity. Naturalistic studies do not point to better outcomes for patients receiving more complex drug regimens, suggesting likely confounding by indication, high severity, or comorbid conditions. Formal clinical trials are needed to identify optimal drug combinations and durations when using ≥ 3 psychotropic medications to treat patients with bipolar disorder.

Tumor Necrosis Factor-Alpha Inhibitor-Associated Psoriatic Alopecia in a Patient with Ulcerative Colitis: A Case Report and Review of the Literature.

Paradoxical reactions in patients treated with tumor necrosis factor-alpha inhibitors (TNFis) have an estimated prevalence of 1.5% to 5%. Such reactions usually present as psoriasiform eruptions on the trunk and extremities along with palmar and flexural involvement. When affecting the scalp, new-onset psoriasis induced by TNFi can result in non-scarring or scarring alopecia. Although the paradoxical reaction was first reported in 2003, this TNFi-associated psoriatic alopecia (TiAPA) has been recently reported with increasing frequency. This condition is characteristically reversible and requires clinical and histopathological identification from other diseases for proper treatment. The cessation of TNFi therapy may not be mandatory, and decision to continue TNFi therapy depends on the severity of TiAPA and the risk-benefit ratio of treatment modification on the underlying disease. Herein, we report a case of TiAPA in a patient with inflammatory bowel disease whose alopecia improved following suspension of TNFi. We also describe the clinical and histopathological diagnostic criteria based on review of the literature.

Utility of flow cytometry and gene rearrangement analysis in tissue and blood of patients with suspected cutaneous T­cell lymphoma.

Cutaneous T­cell lymphoma (CTCL) is difficult to diagnose at an early stage. Current diagnostic tools include clinical examination, histomorphologic analysis, immunohistochemistry, flow cytometry of peripheral blood and/or lesional tissue, and evaluation of T­cell receptor (TCR) clonality by gene rearrangement analysis (TCRGR). Advances in genomic sequencing, including high­throughput sequencing (HTS), can be used to identify specific clones of rearranged TCR genes. Even with all of these tools, CTCL can take as long as a decade to definitively diagnose, potentially delaying treatment options and causing patient anxiety. This study aimed to evaluate the performance of the various ancillary testing modalities used to diagnose early­stage CTCL. In a subset of patients the performance of HTS was compared to flow cytometry and conventional TCRGR analysis via polymerase chain reaction (PCR). Fifty­five patients, with a total of 68 skin biopsies and peripheral blood draws, were evaluated using flow cytometry, PCR­TCRGR, and HTS­TCRGR to determine the sensitivity and specificity of each ancillary test. In tissue biopsies, flow cytometry (64%), PCR (71%) and HTS (69%) shared similar sensitivities; flow cytometry had the highest specificity (93%), followed by HTS (86%) and PCR (76.9%). However, flow cytometry and PCR had insufficient DNA quantities in 29 and 15% of the specimens, respectively. Peripheral blood testing was less sensitive than tissue testing (flow cytometry 14%, PCR 41%, HTS 33%); in peripheral blood, HTS was the most specific test (flow cytometry, 70%; PCR, 62.5%; and HTS, 100%). HTS is a highly specific molecular test for identifying CTCL in peripheral blood and skin biopsy specimens; however, our findings suggest a need for a continued search for more sensitive tests for early­stage CTCL.

Abdominal FLASH irradiation reduces radiation-induced gastrointestinal toxicity for the treatment of ovarian cancer in mice.

Radiation therapy is the most effective cytotoxic therapy for localized tumors. However, normal tissue toxicity limits the radiation dose and the curative potential of radiation therapy when treating larger target volumes. In particular, the highly radiosensitive intestine limits the use of radiation for patients with intra-abdominal tumors. In metastatic ovarian cancer, total abdominal irradiation (TAI) was used as an effective postsurgical adjuvant therapy in the management of abdominal metastases. However, TAI fell out of favor due to high toxicity of the intestine. Here we utilized an innovative preclinical irradiation platform to compare the safety and efficacy of TAI ultra-high dose rate FLASH irradiation to conventional dose rate (CONV) irradiation in mice. We demonstrate that single high dose TAI-FLASH produced less mortality from gastrointestinal syndrome, spared gut function and epithelial integrity, and spared cell death in crypt base columnar cells compared to TAI-CONV irradiation. Importantly, TAI-FLASH and TAI-CONV irradiation had similar efficacy in reducing tumor burden while improving intestinal function in a preclinical model of ovarian cancer metastasis. These findings suggest that FLASH irradiation may be an effective strategy to enhance the therapeutic index of abdominal radiotherapy, with potential application to metastatic ovarian cancer.

Increased local tumor control through nanoparticle-mediated, radiation-triggered release of nitrite, an important precursor for reactive nitrogen species.

The efficacy of dose-enhancing gold nanoparticles (AuNPs) is negatively impacted by low tumor uptake, low cell membrane penetration, limited diffusion distance, and short lifetime of radiation-induced secondary particles. To overcome these limitations, we have developed a novel AuNP system capable of radiation-triggered release of nitrite, a precursor of reactive nitrogen species, and report here on the in vivo characterization of this system. AuNPs were functionalized through PEGylation, cell-penetrating peptides (CPP; AuNP@CPP), and nitroimidazole (nIm; AuNP@nIm-CPP). Mice with subcutaneous 4T1 tumors received either AuNP@nIm-CPP or AuNP@CPP intraperitoneally. Tumor and normal tissue uptake were evaluated 24 h post AuNP administration. A separate cohort of mice was injected and irradiated to a single-fraction dose of 18 Gy in a 225 kVp small animal irradiator 24 h post NP administration. The mice were followed for two weeks to evaluate tumor response. The mean physical and hydrodynamic size of both NP systems were 5 and 13 nm, respectively. NP nIm-loading of 1 wt% was determined. Tumor accumulation of AuNP@nIm-CPP was significantly lower than that of AuNP@CPP (0.2% vs 1.2%, respectively). In contrast, AuNP@nIm-CPP showed higher accumulation compared to AuNP@CPP in liver (16.5% vs 6.6%, respectively) and spleen (10.8% vs 3.1%, respectively). With respect to tumor response, no differential response was found between non-irradiated mice receiving either saline or AuNP@nIm-CPP alone. The combination of AuNP@CPP+ radiation showed no differential response from radiation alone. In contrast, a significant delay in tumor regrowth was observed in mice receiving AuNP@nIm-CPP+ radiation compared to radiation alone. AuNP functionalized with both CPP and nIm exhibited an order of magnitude less tumor accumulation compared to the NP system without nIm yet resulted in a significantly higher therapeutic response. Our data suggest that by improving the biokinetics of AuNP@nIm-CPP, this novel NP system could be a promising radiosensitizer for enhanced therapeutic response following radiation therapy.

Psychopharmacology of COVID-19.

Background: With the rapid, global spread of severe acute respiratory syndrome coronavirus 2, hospitals have become inundated with patients suffering from coronavirus disease 2019. Consultation-liaison psychiatrists are actively involved in managing these patients and should familiarize themselves with how the virus and its proposed treatments can affect psychotropic management. The only Food and Drug Administration-approved drug to treat COVID-19 is remdesivir, and other off-label medications used include chloroquine and hydroxychloroquine, tocilizumab, lopinavir/ritonavir, favipiravir, convalescent plasma therapy, azithromycin, vitamin C, corticosteroids, interferon, and colchicine. Objective: To provide an overview of the major safety considerations relevant to clinicians who prescribe psychotropics to patients with COVID-19, both related to the illness and its proposed treatments. Methods: In this targeted review, we performed structured literature searches in PubMed to identify articles describing the impacts of COVID-19 on different organ systems, the neuropsychiatric adverse effects of treatments, and any potential drug interactions with psychotropics. The articles most relevant to this one were included. Results: COVID-19 impacts multiple organ systems, including gastrointestinal, renal, cardiovascular, pulmonary, immunological, and hematological systems. This may lead to pharmacokinetic changes that impact psychotropic medications and increase sensitivity to psychotropic-related adverse effects. In addition, several proposed treatments for COVID-19 have neuropsychiatric effects and potential interactions with commonly used psychotropics. Conclusions: Clinicians should be aware of the need to adjust existing psychotropics or avoid using certain medications in some patients with COVID-19. They should also be familiar with neuropsychiatric effects of medications being used to treat this disease. Further research is needed to identify strategies to manage psychiatric issues in this population.

Anatomical and dosimetric assessment of the prostate apex: A pilot comparison of image-guided transperineal ultrasound to conventional computed tomography simulation.

INTRODUCTION: Inaccuracies in prostate apex contour delineation based on simulation computed tomography (CT) imaging can impact treatment outcomes and toxicity profiles for prostate cancer radiotherapy. Transperineal ultrasound (TPUS) is a non-invasive imaging modality that can improve delineation of prostate volumes. We performed a pilot analysis to assess for differences in anatomical position between conventional CT and a TPUS delineated prostate apex and determined whether these translated into a clinically significant difference in apical point dose. METHODS: A 2D 5 MHz TPUS autoscan image guidance system was utilised during definitive intensity-modulated radiotherapy (IMRT) for prostate cancer. Distances were measured from a fixed reference point to prostate apex on both US and CT in the mid-sagittal plane. Differences between groups were assessed using the Wilcoxon sign rank test with a two-tailed significance of α = 0.05. RESULTS: Fifty-nine consecutive patients were independently assessed. There was strong evidence of a difference between CT and TPUS delineated apex position (P = 0.0075). Median apex position was 3.6 mm caudal on TPUS vs. CT imaging (95% CI: 2.5-4.8 mm). There was strong evidence of a difference in point dose between CT and TPUS delineated apex (P = 0.0029). Median point dose at the TPUS contoured apex was 1.9 Gy lower than CT (95% CI: 0.7-3.1 Gy) corresponding to 98% of prescribed dose. CONCLUSIONS: This study demonstrates a difference in anatomical delineation of prostate apex position between CT imaging compared to TPUS, corresponding to a statistically significant difference in apex point dose. Further analysis will determine whether this translates to a clinically significant difference in outcomes.

E-Cigarette, Cigarette, and Dual Use in Korean Adolescents: A Test of Problem Behavior Theory.

E-cigarettes are becoming increasingly popular among adolescent cigarette users. However, little is known about the various factors related to adolescents' use of e-cigarettes, cigarettes, or both in South Korea. Using nationally representative data from the 2017 Korea Youth Risk Behavior Web-based Survey, this study examined the possible problem behavior theory factors that contribute to (1) current e-cigarette use among those who have ever used cigarettes (Model 1), (2) current cigarette use among those who have ever used e-cigarettes (Model 2), and (3) current dual use among current cigarette or e-cigarette users (Model 3). In all three models, our analysis showed that tobacco accessibility and sexual intercourse were significant factors. For Model 2, reasons for using e-cigarettes and alcohol use were correlated with current cigarette use. Except for gender, the significant factors, which included secondhand smoke exposure at home and school type, were the same in Models 1 and 3. Based on these findings, we encourage the South Korean government to pay close attention to potential increase in dual use among adolescents and to take the necessary steps in addressing adolescent e-cigarette use in tobacco prevention and control programs.

Eccrine Porocarcinoma: A Multicenter Retrospective Study with Review of the Literatures Reported in Korea.

BACKGROUND: Eccrine porocarcinoma (EPC) is a rare malignant cutaneous adnexal tumor. Other than several scattered case reports, no comprehensive review on EPC has been conducted in Korea. OBJECTIVE: To clinicopathologically review all EPC cases from our institutions as well as those reported in Korea. METHODS: Medical records and histopathological slides of EPC cases in the skin biopsy registries of our institutions were retrospectively reviewed. Additionally, EPC cases reported in Korea before June 2019 were retrieved by searching the PubMed, KoMCI, KoreaMed, and KMbase databases. RESULTS: Nine EPC cases from our institutions were included in the study. In addition, 27 reports of 28 patients with EPC were reported in Korea. A total of 37 patients with EPC were identified, consisting of 19 males (male:female ratio, 1.06:1; mean age at diagnosis, 65.6 years). The most common site of primary tumor was the head and neck (29.7%). Wide excision was the most common (78.4%) treatment method. Initial metastasis work-up imaging studies were performed in 18 patients (48.6%), and metastasis was confirmed in eight patients (21.6%). CONCLUSION: EPC is a rare cutaneous carcinoma in Korea. EPC usually affects elderly patients, with no sexual predilection. Due to possible metastasis, careful diagnosis and appropriate metastasis work-ups are warranted in EPC.

Retinal VEGFA maintains the ultrastructure and function of choriocapillaris by preserving the endothelial PLVAP.

Fenestrations in choriocapillaris act as a window for molecular transports between the retina and choroid, and is crucial for maintaining visual function. Plasmalemma vesicle-associated protein (PLVAP) is essential for the development of endothelial fenestrations. There is little knowledge about how the choriocapillaris maintains the fenestrated endothelium. This study aimed to evaluate the role of vascular endothelial growth factor-A (VEGFA)-PLVAP axis in the maintenance of choroidal fenestrations using oxygen-induced retinopathy (OIR) model. In C57BL/6 J mice, the mice with OIR on postnatal day 12 (P12) presented thicker endothelium and less fenestration compared to the non-OIR mice. However, the OIR on 17 mice showed thinner endothelium with more fenestration compared to OIR on P12. In vivo angiography demonstrated the presence of hyperpermeable choroidal vessels on P17 in OIR mice. These dramatic changes in choriocapillaris were not observed in the BALB/cJ OIR model. The ultrastructural changes in the choriocapillaris were correlated with temporal variations in the expression of VEGFA and PLVAP. VEGFA stimulated expression of PLVAP in the choroidal endothelial cells. Loss of PLVAP disrupts the polarized structure of the choriocapillaris leading to retinal degeneration. These results indicate that the expression of retinal VEGFA is essential for maintaining the structure and function of choriocapillaris by preserving the endothelial PLVAP.

Reduced cognitive deficits after FLASH irradiation of whole mouse brain are associated with less hippocampal dendritic spine loss and neuroinflammation.

AIM: To evaluate the impact of ultra-rapid FLASH mouse whole brain irradiation on hippocampal dendritic spines and neuroinflammation, factors associated with cognitive impairment after brain irradiation. METHODS: We administered 30 Gy whole brain irradiation to C57BL6/J mice in sub-second (FLASH) vs. 240 s conventional delivery time keeping all other parameters constant, using a custom configured clinical linac. Ten weeks post-irradiation, we evaluated spatial and non-spatial object recognition using novel object location and object recognition testing. We measured dendritic spine density by tracing Golgi-stained hippocampal neurons and evaluated neuroinflammation by CD68 immunostaining, a marker of activated microglia, and expression of 10 pro-inflammatory cytokines using a multiplex immunoassay. RESULTS: At ten weeks post-irradiation, compared to unirradiated controls, conventional delivery time irradiation significantly impaired novel object location and recognition tasks whereas the same dose given in FLASH delivery did not. Conventional delivery time, but not FLASH, was associated with significant loss of dendritic spine density in hippocampal apical dendrites, with a similar non-significant trend in basal dendrites. Conventional delivery time was associated with significantly increased CD68-positive microglia compared to controls whereas FLASH was not. Conventional delivery time was associated with significant increases in 5 of 10 pro-inflammatory cytokines in the hippocampus (and non-significant increases in another 3), whereas FLASH was associated with smaller increases in only 3. CONCLUSION: Reduced cognitive impairment and associated neurodegeneration were observed with FLASH compared to conventional delivery time irradiation, potentially through decreased induction of neuroinflammation, suggesting a promising approach to increasing therapeutic index in radiation therapy of brain tumors.

FANCA Promotes DNA Double-Strand Break Repair by Catalyzing Single-Strand Annealing and Strand Exchange.

FANCA is a component of the Fanconi anemia (FA) core complex that activates DNA interstrand crosslink repair by monoubiquitination of FANCD2. Here, we report that purified FANCA protein catalyzes bidirectional single-strand annealing (SA) and strand exchange (SE) at a level comparable to RAD52, while a disease-causing FANCA mutant, F1263Δ, is defective in both activities. FANCG, which directly interacts with FANCA, dramatically stimulates its SA and SE activities. Alternatively, FANCB, which does not directly interact with FANCA, does not stimulate this activity. Importantly, five other patient-derived FANCA mutants also exhibit deficient SA and SE, suggesting that the biochemical activities of FANCA are relevant to the etiology of FA. A cell-based DNA double-strand break (DSB) repair assay demonstrates that FANCA plays a direct role in the single-strand annealing sub-pathway (SSA) of DSB repair by catalyzing SA, and this role is independent of the canonical FA pathway and RAD52.