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Background: Over the past decade, the adoption of screening programs, digital mammography, and magnetic resonance imaging (MRI) has increased early-stage breast cancer diagnosis rates. Mortality rates have decreased due to early detection and improved treatments, including personalized therapies. Accelerated partial-breast irradiation (APBI) is emerging as a convenient and effective treatment for some patients, with studies exploring its preoperative use. Preoperative APBI, especially with MRI guidance, offers improved tumor targeting and potentially reduced side effects. Magnetic Resonance Imaging-Guided Single-Fraction Pre-Operative Radiotherapy for Early-Stage Breast Cancer (RICE trial) aims to assess the feasibility and efficacy of MRI-guided single-dose radiotherapy (RT) for early-stage breast cancer., Methods: The RICE study is a prospective, single-arm study evaluating single-fraction preoperative, APBI treatment for patients with early-stage breast cancer using a magnetic resonance imaging linear accelerator (MRI linac). Eligible patients enrolled in this study will have a core biopsy to confirm estrogen receptor-positive and HER2-negative sub-type. RT planning will use a planning computed tomography (CT) co-registered with a MRI with the patient in either the supine or prone position. For the diagnostic workup, [18F] fluorodeoxyglucose positron emission tomography/CT ([18F] FDG PET/CT) and [18F] fluoroestradiol positron emission tomography/CT ([18F] FES PET/CT) will be performed prior to treatment. Thirty patients will receive a single ablative RT dose of 21 Gray to the tumor. Pre-treatment and post-treatment MRI scans will be acquired at baseline and 5 weeks post-RT respectively. Breast-conserving surgery will be scheduled for 6 weeks after APBI treatment using the MRI linac. The primary study endpoint is the successful administration of a single fraction of preoperative breast RT under the guidance of an MRI linac. Secondary endpoints include evaluating the utility of MRI, [18F] FDG PET/CT, and [18F] FES PET/CT as a non-invasive method for assessing treatment response in patients undergoing single-fraction preoperative APBI., Conclusion: The RICE trial represents a significant step in breast cancer treatment, offering insights that could lead to treatment protocols with minimized RT appointments and enhanced patient outcomes., Trial Registration: This trial is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR). Registered 31st of May 2021., Registration Number: ACTRN12621000659808 ., (© 2024. The Author(s).)

Background: Pediatric critical illness exposes family members to stressful experiences that may lead to subsequent psychological repercussions., Objective: To systematically review psychological outcomes among PICU survivors' family members., Data Sources: Four medical databases (PubMed, Embase, CINAHL and PsycInfo) were searched from inception till October 2023., Study Selection: Studies reporting psychological disorders in family members of PICU patients with at least 3 months follow-up were included. Family members of nonsurvivors and palliative care patients were excluded., Data Extraction: Screening and data extraction was performed according to PRISMA guidelines. Data were pooled using a random-effects model., Results: Of 5360 articles identified, 4 randomized controlled trials, 16 cohort studies, and 2 cross-sectional studies were included (total patients = 55 597; total family members = 97 506). Psychological distress was reported in 35.2% to 64.3% and 40.9% to 53% of family members 3 to 6 months and 1 year after their child's PICU admission, respectively. Post-traumatic stress disorder was diagnosed in 10% to 48% of parents 3 to 9 months later. Parents that experienced moderate to severe anxiety and depression 3 to 6 months later was 20.9% to 42% and 6.1% to 42.6%, respectively. Uptake of mental counseling among parents was disproportionately low at 0.7% to 29%. Risk factors for psychiatric morbidity include mothers, parents of younger children, and longer duration of PICU stay., Limitations: The majority of studies were on parents with limited data on siblings and second degree relatives., Conclusions: There is a high burden of psychological sequelae in family members of PICU survivors. Risk stratification to identify high-risk groups and early interventions are needed., (Copyright © 2024 by the American Academy of Pediatrics.)

Introduction: Consistent delineation of the breast conserving surgery (BCS) tumour bed (TB) for breast cancer remains a challenge for radiation oncologists. Accurate delineation allows for better local control and reduces toxicity when planning partial breast or TB boost radiation therapy (RT)., Methods: In the operating theatre (OT) breast surgeons inserted stabilised hyaluronic acid (sHA) gel as small drops approximately one cm into the walls surrounding the resection cavity. Surgical feasibility was determined by the rate of successful sHA gel insertion procedure, the ease of insertion as rated by surgeons, the time required for insertion procedure, the quantity used, and any adverse events (AE) relating to sHA gel insertion., Results: Thirty-five patients were enrolled. All patients underwent sHA gel insertion successfully. The procedure added a median of 2.8 min to the OT time and was rated as 'easy' in 89 % of patients. There were no immediate AE in OT. Five (14 %) patients experienced a grade 2 or higher AE. Three of the five patients were prescribed oral antibiotics for breast infection. Two of the five patients experienced a grade 3 AE - haematoma which required evacuation in OT day 1 post-BCS, and infected seroma which required drainage and washout in OT 2 months post-BCS. All five patients recovered and underwent the planned adjuvant therapies for their BC. The AE data reflects common risks with standard BCS and are not clearly attributed to sHA gel insertion alone., Conclusion: We show that sHA gel is surgically feasible as a marker to help define the TB cavity for post-BCS adjuvant MRI-based RT planning., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘Michael Chao reports equipment, drugs, or supplies was provided by Palette Life Sciences. Michael Chao reports a relationship with Palette Life Sciences that includes: consulting or advisory.’., (© 2024 The Author(s).)

Background: Recent research has demonstrated that machine learning (ML) has the potential to improve several aspects of medical application for critical illness, including sepsis. This scoping review aims to evaluate the feasibility of probabilistic graphical model (PGM) methods in pediatric sepsis application and describe the use of pediatric sepsis definition in these studies., Methods: Literature searches were conducted in PubMed, Scopus, Cumulative Index to Nursing and Allied Health Literature (CINAHL+), and Web of Sciences from 2000-2023. Keywords included "pediatric", "neonates", "infants", "machine learning", "probabilistic graphical model", and "sepsis"., Results: A total of 3,244 studies were screened, and 72 were included in this scoping review. Sepsis was defined using positive microbiology cultures in 19 studies (26.4%), followed by the 2005's international pediatric sepsis consensus definition in 11 studies (15.3%), and Sepsis-3 definition in seven studies (9.7%). Other sepsis definitions included: bacterial infection, the international classification of diseases, clinicians' assessment, and antibiotic administration time. Among the most common ML approaches used were logistic regression (n=27), random forest (n=24), and Neural Network (n=18). PGMs were used in 13 studies (18.1%), including Bayesian classifiers (n=10), and the Markov Model (n=3). When applied on the same dataset, PGMs show a relatively inferior performance to other ML models in most cases. Other aspects of explainability and transparency were not examined in these studies., Conclusions: Current studies suggest that the performance of probabilistic graphic models is relatively inferior to other ML methods. However, its explainability and transparency advantages make it a potentially viable method for several pediatric sepsis studies and applications., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-23-25/coif). All authors report this study has received payment from National Research Medical Council, Singapore. J.H.L. is serving as a Deputy Editor-in-Chief of Translational Pediatrics from July 2022 to June 2024. The authors have no other conflicts of interest to declare., (2023 Translational Pediatrics. All rights reserved.)

Purpose: To assess the degree of pathologic complete response (pCR), postoperative surgical complication rates, and oncological outcomes in women with locally advanced breast cancer or high-risk breast cancers treated with neoadjuvant radiation therapy (NART)., Methods and Materials: This retrospective, multi-institutional review involved 138 clinically staged patients with 140 breast cancers treated with NART between January 2014 and February 2021. Treatments involved sequential neoadjuvant chemotherapy and NART, followed by mastectomy with or without axillary surgery and immediate autologous breast reconstruction. Descriptive statistics were used to assess patient and disease features, treatment regimens, pathologic response, and factors affecting postoperative complications. Kaplan-Meier curves were performed to assess locoregional recurrence-free, distant metastasis-free, and overall survival outcomes., Results: Median age was 47 years (interquartile range, 42-52). The median follow-up was 35.2 months (interquartile range, 17.1-46.5). pCR was achieved in 36.4% (as defined by Chevallier classification) or 42.1% (as defined by Miller-Payne scores) of patients. Greater pCR rates were achieved for HER2+ (73.8%-85.7%) and triple-negative phenotypes (47.6%-57.1%). There were 21 grade 3 surgical complications including 10 grade 3B breast events and 8 grade 3B donor-site events, where surgical reintervention was required. At 3-years' follow-up, the locoregional recurrence-free survival was 98.1%, distant metastasis-free survival was 83.6%, and overall survival was 95.3%%., Conclusions: NART is feasible to facilitate a single-stage mastectomy and immediate autologous breast reconstruction. This study demonstrated comparable rates of postoperative complication to standard of care, and high rates of pCR, which translates to high rates of locoregional control, distant metastasis-free survival, and overall survival., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Palliative care (PC) is an integral component of optimal critical care (CC) practice for pediatric patients facing life-threatening illness. PC acts as an additional resource for patients and families as they navigate through critical illness. Although PC encompasses end of life care, it is most effective when integrated early alongside disease-directed and curative therapies. PC primarily focuses on improving quality of life for patients and families by anticipating, preventing and treating suffering throughout the continuum of illness. This includes addressing symptom distress and facilitating communication. Effective communication is vital to elicit value-based goals of care, and to guide parents through patient-focused and potentially difficult decision-making process which includes advanced care planning. A multidisciplinary approach is most favorable when providing support to both patient and family, whether it is from the psychosocial, practical, emotional, spiritual or cultural aspects. PC also ensures coordination and continuity of care across different care settings. Support for family carries on after death with grief and bereavement support. This narrative review aims to appraise the current evidence of integration of PC into pediatric CC and its impact on patient- and family-centered outcomes. We will also summarize the impact of integration of good PC into pediatric CC, including effective communication with families, advanced care planning, withholding or withdrawal of life sustaining measures and bereavement support. Finally, we will provide a framework on how best to integrate PC in PICU. These findings will provide insights on how PC can improve the quality of care of a critically ill child., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Buang, Loh, Mok, Lee and Chan.)

Nutritional practice in children with severe sepsis or septic shock remains poorly described. We aimed to describe nutrition received by children with severe sepsis or septic shock and explore the association of nutritional intake with clinical outcomes. This study was a retrospective study of children who required pediatric intensive care unit (PICU) admission from 2009 to 2016. Outcomes were mortality, ventilator-free days (VFDs), and PICU-free days (IFDs). A total of 74 patients with septic shock or severe sepsis were identified. Forty-one (55.4%) patients received enteral nutrition (EN) only, 6 (8.1%) patients received parental nutrition (PN) only, 15 (20.3%) patients received both EN and PN, and 12 (16.2%) patients received intravenous fluids alone. Eight of 74 (10.8%) and 4 of 74 (5.4%) had adequate energy and protein intake, respectively. Patients who received early EN had lower odds of 28-day mortality (adjusted hazard ratio [HR] = 0.09, 95% confidence interval [CI]: 0.02, 0.45, p  = 0.03) more 28-day VFDs (adjusted β-coefficient = 18.21 [95% CI: 11.11, 25.32], p  < 0.001), and IFDs (adjusted ß-coefficient = 16.71 [95% CI: 9.86, 23.56], p  < 0.001) than patients who did not receive EN. Late EN was also associated with lower odds of mortality, more VFDs, and IFDs compared with no EN (HR = 0.06, 95% CI: 0.02, 0.23; p  < 0.001; adjusted β coefficient = 15.66, 95% CI: 9.31, 22.02; p  < 0.001; and 12.34 [95% CI: 6.22, 18.46], p  < 0.001; respectively). Inadequate calories and protein were not associated with mortality. EN in children with septic shock or severe sepsis was associated with improved clinical outcomes. Future prospective studies are required to explore the impact of EN timing and optimal nutritional intake in these children., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

Introduction: With improving mortality rates in pediatric acute respiratory distress syndrome (PARDS), functional outcomes in survivors are increasingly important. We aim to describe the change in functional status score (FSS) from baseline to discharge and to identify risk factors associated with poor functional outcomes., Methods: We examined clinical records of patients with PARDS admitted to our pediatric intensive care unit (PICU) from 2009 to 2016. Our primary outcome was acquired morbidity at PICU and hospital discharge (defined by an increase in FSS ≥3 points above baseline). We included severity of illness scores and severity of PARDS in our bivariate analysis for risk factors for acquired morbidity., Results: There were 181 patients with PARDS, of which 90 (49.7%) survived. Median pediatric index of mortality 2 score was 4.05 (1.22, 8.70) and 21 (23.3%) survivors had severe PARDS. A total of 59 (65.6%) and 14 (15.6%) patients had acquired morbidity at PICU and hospital discharge, respectively. Median baseline FSS was 6.00 (6.00, 6.25), which increased to 11.00 (8.75, 12.00) at PICU discharge before decreasing to 7.50 (6.00, 9.25) at hospital discharge. All patients had significantly higher FSS at both PICU and hospital discharge median compared to baseline. Feeding and respiratory were the most affected domains. After adjusting for severity of illness, severity categories of PARDS were not a risk factor for acquired morbidity., Conclusion: Acquired morbidity in respiratory and feeding domains was common in PARDS survivors. Specific attention should be given to these two domains of functional outcomes in these children., (© 2021 Wiley Periodicals LLC.)

Introduction: Neoadjuvant radiotherapy (NART) as part of a multi-modality approach for locally advanced breast cancer (LABC) requires further investigation. Importantly, this approach may allow for a single-staged surgical procedure, with mastectomy and immediate autologous reconstruction. Multiple other potential benefits of NART include improved pathological downstaging of breast disease, reduced overall treatment time, elimination of time period with breast tissue deficit and improved patient satisfaction., Methods: This is a retrospective multi-institutional review of patients with LABC and high-risk breast disease undergoing NART. Eligible patients sequentially underwent neoadjuvant chemotherapy (NACT) with or without HER2-targeted therapy, NART, followed by mastectomy with immediate autologous breast reconstruction (BR) 4- to 6 weeks post-completion of radiotherapy. Patient and tumour characteristics were analysed using descriptive statistics. Surgical complications were assessed using the Clavien-Dindo Classification (Ann Surg 2004; 240: 205)., Results: From 3/2013 to 9/2019, 153 patients were treated with NART. The median age was 47 years (IQR 42-52), with median body mass index of 27. Eighteen patients experienced Grade 3 acute surgical complications. This included 13 Grade 3B breast-site events and 9 Grade 3B donor-site events, where further surgical intervention was required for management of wound infection, wound dehiscence, flap or mastectomy skin necrosis, haematoma and internal mammary venous anastomotic thrombosis. No autologous flap loss was observed., Conclusion: Neoadjuvant radiotherapy facilitates a single-stage surgical procedure with mastectomy and immediate autologous BR, eliminating the delay to reconstructive surgery and thus shortening a woman's breast cancer journey. The findings of this review support the use of NART, with comparable rates of surgical complications to standard sequencing., (© 2021 The Royal Australian and New Zealand College of Radiologists.)

Purpose: To determine the diagnostic parameters of breast ultrasound (US) in the setting of routine radiological surveillance after a diagnosis of breast cancer and evaluate costs of the inclusion of breast US as well as any survival benefit of US detected cases of recurrence in surveillance., Methods: 622 patients underwent breast cancer surgery and follow up at Austin Health from July 2009 to December 2015. Retrospective data analysis was performed to determine; diagnostic parameters, financial costs of US and survival outcomes of US detected cases of recurrence., Results: Patients underwent 1-9 years of breast cancer surveillance, with a median of 4.24 years. 390 (62.7%) patients underwent additional breast US surveillance to mammography. 232 (38.3%) fit criteria for use of additional breast US. 199 abnormal imaging episodes occurred, leading to 16 screen detected-cases of locoregional recurrence. US alone generated 107 abnormal images and found 9 cancers. US had a sensitivity of 44.1%, specificity of 95.2% and positive predictive value of 11.7% in comparison to mammography; 20.6%, 97.4% and 9.9% respectively. US had a biopsy rate of 4.0% and lead to an incremental cancer detection rate of 0.38%. The cost of incremental cancer found was $31,463.72 AUD. Survival outcomes based on method of detection of recurrence were insignificant (p value = 0.71)., Conclusions: Breast US has a sensitivity of 44.1% and detected seven recurrences that were mammographically occult. Breast US has a similar PPV to mammography in surveillance. Breast US generated considerable biopsy rates and costs. Survival analysis was not able to detect any benefit of US detected cases of recurrence., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Prone position is known to improve mortality in patients with acute respiratory distress syndrome (ARDS). The impact of prone position in critically ill patients with coronavirus disease of 2019 (COVID-19) remains to be determined. In this review, we describe the mechanisms of action of prone position, systematically appraise the current experience of prone position in COVID-19 patients, and highlight unique considerations for prone position practices during this pandemic., Methods: For our systematic review, we searched PubMed, Scopus and EMBASE from January 1, 2020, to April 16, 2020. After completion of our search, we became aware of four relevant publications during article preparation that were published in May and June 2020, and these studies were reviewed for eligibility and inclusion. We included all studies reporting clinical characteristics of patients admitted to the hospital with COVID-19 disease who received respiratory support with high-flow nasal cannula, or noninvasive or mechanical ventilation and reported the use of prone position. The full text of eligible articles was reviewed, and data regarding study design, patient characteristics, interventions and outcomes were extracted., Results: We found seven studies (total 1899 patients) describing prone position in COVID-19. Prone position has been increasingly used in non-intubated patients with COVID-19; studies show high tolerance and improvement in oxygenation and lung recruitment. Published studies lacked a description of important clinical outcomes (e.g., mortality, duration of mechanical ventilation)., Conclusions: Based on the findings of our review, we recommend prone position in patients with moderate to severe COVID-19 ARDS as per existing guidelines. A trial of prone position should be considered for non-intubated COVID-19 patients with hypoxemic respiratory failure, as long as this does not result in a delay in intubation.

Background . Tuberculosis (TB) remains a major cause of mortality and morbidity globally. Pediatric patients are more likely to develop severe disease. Abdominal TB is a rare manifestation of pediatric TB and can present with chronic and nonspecific abdominal symptoms. This study examines the clinical profile of pediatric patients with abdominal TB and treatment outcomes. Method . A retrospective study of patients admitted to a tertiary pediatric hospital in Singapore over 10 years. Clinical characteristics and outcomes were examined. Results. There were 3 male and 3 female patients with mean age of 11.3 years. Household contacts were traced in 3 cases. The most common presenting symptoms were fever, weight loss, and abdominal symptoms such as diarrhea, vomiting, and loss of appetite. Inflammatory markers were raised with mean C-reactive protein (CRP) and erythrocyte sedimentation (ESR) rate at 70.9 mg/L and 90 mm/h respectively. Abdominal imaging showed abnormalities such as splenic foci and thickened bowel wall with significant intraabdominal lymphadenopathy. Mycobacterium tuberculosis was isolated from stool, rectal swabs and intra-adominal specimens. Two patients underwent excisional biopsy of lymph node to obtain diagnosis. Two patients required emergency laparotomy and 1 patient received esophagogastroduodenoscopy and colonoscopy. Four out of the 6 patients had pulmonary involvement. Conclusion . Abdominal TB should be a differential diagnosis in children with chronic abdominal symptoms for at least 8 weeks with anemia, raised ESR and CRP. The gold standard for diagnosis still remains as positive microbiological culture. However, abdominal imaging studies are also vital in obtaining further supportive evidence for chronic infection., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

The objectives of this review are to describe the limitations of commonly used clinical outcomes [e.g., mortality, ventilation parameters, need for extracorporeal membrane oxygenation (ECMO), pediatric intensive care unit (PICU) and hospital length of stay (LOS)] in pediatric acute respiratory distress syndrome (PARDS) studies; and to explore other pertinent clinical outcomes that pediatric critical care practitioners should consider in future clinical practice and research studies. These include long-term pulmonary function, risk of pulmonary hypertension (PHT), nutrition status and growth, PICU-acquired weakness, neurological outcomes and neurocognitive development, functional status, health-related quality of life (HRQOL)], health-care costs, caregiver and family stress. PubMed was searched using the following keywords or medical subject headings (MESH): "acute lung injury (ALI)", "acute respiratory distress syndrome (ARDS)", "pediatric acute respiratory distress syndrome (PARDS)", "acute hypoxemia respiratory failure", "outcomes", "pediatric intensive care unit (PICU)", "lung function", "pulmonary hypertension", "growth", "nutrition', "steroid", "PICU-acquired weakness", "functional status scale", "neurocognitive", "psychology", "health-care expenditure", and "HRQOL". The concept of contemporary measure outcomes was adapted from adult ARDS long-term outcome studies. Articles were initially searched from existing PARDS articles pool. If the relevant measure outcomes were not found, where appropriate, we considered studies from non-ARDS patients within the PICU in whom these outcomes were studied. Long-term outcomes in survivors of PARDS were not follow-up in majority of pediatric studies regardless of whether the new or old definitions of ARDS in children were used. Relevant studies were scarce, and the number of participants was small. As such, available studies were not able to provide conclusive answers to most of our clinical queries. There remains a paucity of data on contemporary clinical outcomes in PARDS studies. In addition to the current commonly used outcomes, clinical researchers and investigators should consider examining these contemporary outcome measures in PARDS studies in the future., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Annals of Translational Medicine. All rights reserved.)

Background: Tuberculosis (TB) is a major cause of mortality and morbidity in the world. Each case represents ongoing transmission and has a significant public health burden. We aim to examine the clinical profile of paediatric TB and compare pulmonary TB (PTB) with extrapulmonary TB (EPTB) in Singapore., Methods: A retrospective study of patients admitted to KK Women's and Children's Hospital, Singapore from January 2008 to September 2017 with active TB was undertaken. The clinical characteristics and outcomes of patients with PTB and EPTB were compared., Results: Seventy-five patients were diagnosed as having active TB (49 (65%) with PTB and 26 (35%) with EPTB). Patients with EPTB were more likely than those with PTB to be younger (median age 5.1 (IQR 1.2-10.2) years vs 10.1 (IQR 3.5-13.5) years), immunodeficient (35% vs 6%), with a lower haemoglobin count (median 11.2 (IQR 10.2-11.9) g/dL vs 12.0 (IQR 10.5-13.9) g/dL), lower recovery rate (27% vs 57%) and required longer duration of treatment (median 12 (IQR 9-12) months vs 6 (IQR 6-9) months). Common clinical presentations of both PTB and EPTB were significant fever (27%), cough (33%) and weight loss (32%). Overall mortality was 8% with septic shock responsible for three of the six deaths., Conclusion: EPTB is more common in the younger age group and is associated with a lower recovery rate., Competing Interests: Competing interests: None declared.

We report a case of an infant who had presented with fever and an acral-accentuated rash, for which his cerebrospinal fluid returned positive for parechovirus. He was treated symptomatically and discharged well, with no long-term complications., (© 2017 Wiley Periodicals, Inc.)

TNF-induced signaling mediates pleiotropic biological consequences including inflammation, immunity, cell proliferation and apoptosis. Misregulation of TNF signaling has been attributed as a major cause of chronic inflammatory diseases and cancer. Jumonji domain-containing protein 8 (JMJD8) belongs to the JmjC family. However, only part of the family members has been described as hydroxylase enzymes that function as histone demethylases. Here, we report that JMJD8 positively regulates TNF-induced NF-κB signaling. Silencing the expression of JMJD8 using RNA interference (RNAi) greatly suppresses TNF-induced expression of several NF-κB-dependent genes. Furthermore, knockdown of JMJD8 expression reduces RIP ubiquitination, IKK kinase activity, delays IκBα degradation and subsequently blocks nuclear translocation of p65. In addition, JMJD8 deficiency enhances TNF-induced apoptosis. Taken together, these findings indicate that JMJD8 functions as a positive regulator of TNF-induced NF-κB signaling.

Emerging of drug resistant influenza A virus (IAV) has been a big challenge for anti-IAV therapy. In this study, we describe a relatively easy and safe cell-based screening system for anti-IAV replication inhibitors using a non-replicative strain of IAV. A nickel (II) complex of polyhydroxybenzaldehyde N4-thiosemicarbazone (NiPT5) was recently found to exhibit anti-inflammatory activity in vivo and in vitro. NiPT5 impedes the signaling cascades that lead to the activation of NF-κB in response to different stimuli, such as LPS and TNFα. Using our cell-based screening system, we report that pretreating cells with NiPT5 protects cells from influenza A virus (IAV) and vesicular stomatitis virus (VSV) infection. Furthermore, NiPT5 inhibits replication of IAV by inhibiting transcription and translation of vRNAs of IAV. Additionally, NiPT5 reduces IAV-induced type I interferon response and cytokines production. Moreover, NiPT5 prevents activation of NF-κB, and IRF3 in response to IAV infection. These results demonstrate that NiPT5 is a potent antiviral agent that inhibits the early phase of IAV replication.

Background: H3K9 methylation is one of the essential histone post-translational modifications for heterochromatin formation and transcriptional repression. Recently, several studies have demonstrated that H3K9 methylation negatively regulates the type I interferon response., Results: We report the application of EHMT1 and EHMT2 specific chemical inhibitors to sensitize CML cell lines to interferon and imatinib treatments. Inhibition of EHMT1 and EHMT2 with BIX01294 enhances the cytotoxicity of IFNα2a in four CML cell lines, K562, KCL22, BV173 and KT1 cells. Chromatin immunoprecipitation assay shows that BIX01294 treatment enhances type I interferon response by reducing H3K9me2 at the promoters of interferon-stimulated genes. Additionally, BIX01294 treatment augments IFNα2a- and imatinib-mediated apoptosis in CML cell lines. Moreover, our data suggest that the expression level of EHMT1 and EHMT2 inversely correlates with the type I interferon responsiveness in CML cell lines., Conclusions: Our study sheds light on the role of EHMT1 and EHMT2 as potential targets in improving the efficacy of standard treatments of CML.

Background: The biological properties of thiosemicarbazone have been widely reported. The incorporation of some transition metals such as Fe, Ni and Cu to thiosemicarbazone complexes is known to enhance its biological effects. In this study, we incorporated nickel(II) ions into thiosemicarbazone with N4-substitution groups H3L (H; H3L1, CH3; H3L2, C6H5; H3L3 and C2H5; H3L4) and examined its potential anti-inflammatory activity., Methodology/principal Findings: Four ligands (1-4) and their respective nickel-containing complexes (5-8) were synthesized and characterized. The compounds synthesized were tested for their effects on NF-κB nuclear translocation, pro-inflammatory cytokines secretion and NF-κB transactivation activity. The active compound was further evaluated on its ability to suppress carrageenan-induced acute inflammation in vivo. A potential binding target of the active compound was also predicted by molecular docking analysis., Conclusions/significance: Among all synthesized compounds tested, we found that complex [Ni(H2L1)(PPh3)]Cl (5) (complex 5), potently inhibited IκBα degradation and NF-κB p65 nuclear translocation in LPS-stimulated RAW264.7 cells as well as TNFα-stimulated HeLa S3 cells. In addition, complex 5 significantly down-regulated LPS- or TNFα-induced transcription of NF-κB target genes, including genes that encode the pro-inflammatory cytokines TNFα, IFNβ and IL6. Luciferase reporter assays confirmed that complex 5 inhibited the transactivation activity of NF-κB. Furthermore, the anti-inflammatory effect of complex 5 was also supported by its suppressive effect on carrageenan-induced paw edema formation in wild type C57BL/6 mice. Interestingly, molecular docking study showed that complex 5 potentially interact with the active site of IKKβ. Taken together, we suggest complex 5 as a novel NF-κB inhibitor with potent anti-inflammatory effects.

Background: There is now increasing evidence to support the use of indocyanine green (ICG) for sentinel lymph node (SLN) detection in early breast cancer. The primary objective of this feasibility study (ICG-10) was to determine the sensitivity and safety of ICG fluorescence imaging in sentinel lymph node identification when combined with blue dye and radiocolloid., Methods: One hundred women with clinically node negative breast cancer (95 unilateral; 5 bilateral) had sentinel lymph node (SLN) biopsy using blue dye, radioisotope and ICG. One patient was excluded from analysis and sensitivity, or detection rate, of ICG alone, and in combination with blue dye and/or radioisotope, was calculated for the remaining 104 procedures in 99 patients., Results: Transcutaneous fluorescent lymphography was visible in all 104 procedures. All 202 true SLNs, defined as blue and/or radioactive, were also fluorescent with ICG. Detection rates were: ICG alone 100%, ICG & blue dye 95.0%, ICG & radioisotope 77.2%, ICG & blue dye & radioisotope 73.1%. Metastases were found in 25 of 201 SLNs (12.4%) and all positive nodes were fluorescent, blue and radioactive. The procedural node positivity rate was 17.3%., Conclusion: The results of this study confirm the high sensitivity of ICG fluorescence for SLN detection in early breast cancer. The combination of ICG and blue dye had the highest nodal sensitivity at 95.0% defining a dual approach to SLN biopsy that avoids the need for radioisotope., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The peptide hormone gastrin binds two ferric ions with high affinity, and iron binding is essential for the biological activity of non-amidated gastrins in vitro and in vivo. Bi3+ ions also bind to glycine-extended gastrin17 (Ggly), but inhibit Ggly-induced cell proliferation and migration in gastrointestinal cell lines in vitro. The aims of the present study were firstly, to establish the mechanism by which Bi3+ ions inhibit the binding of Fe3+ ions to Ggly, and secondly, to test the effect of Bi3+ ions on the activity of non-amidated gastrins in vivo. The interaction between Bi3+ ions, Fe3+ ions and Ggly was investigated by ultraviolet spectroscopy. The effect of Bi3+ ions on colorectal mucosal proliferation was measured in three animal models. In vitro in the presence of Bi3+ ions the affinity of Fe3+ ions for Ggly was substantially reduced; the data was better fitted by a mixed, rather than a competitive, inhibition model. In rats treated with Ggly alone proliferation in the rectal mucosa was increased by 318%, but was reduced to control values (p < 0.001) in animals receiving oral bismuth plus Ggly. Proliferation in the colonic mucosa of mice overexpressing Ggly or progastrin was significantly greater than in wild-type mice, but was no greater than control (p < 0.01) in animals receiving oral bismuth. Thus a reduction in the binding of Fe3+ ions to Ggly and progastrin in the presence of Bi3+ ions is a likely explanation for the ability of oral bismuth to block the biological activity of non-amidated gastrins in vivo., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Although there is abundant evidence that gastrin-releasing peptide acts as a mitogen in various carcinoma cell lines, the effect of administration of gastrin-releasing peptide on the colorectal mucosa in vivo has not been reported. The aims of this study were to determine whether continuous infusion of gastrin-releasing peptide stimulated proliferation or accelerated carcinogenesis in the rat gastrointestinal tract and other organs. The possible requirement for C-terminal amidation for mitogenic activity in vivo was also investigated. Proliferation was measured in the colon by metaphase index and by immunostaining for the proliferation marker Ki-67, and in other tissues by immunostaining alone. Acceleration of colorectal carcinogenesis was assessed by counting aberrant crypt foci after treatment with the carcinogen azoxymethane. Defunctioning of the rectum reduced both the proliferative index and the crypt height of the rectal mucosa of untreated rats. Treatment with amidated or glycine-extended gastrin-releasing peptide for 4 weeks using implanted mini-osmotic pumps resulted in a two- to three-fold increase in proliferation, and an increase in crypt height, in the defunctioned rectal mucosa (p<0.001), with smaller but significant increases in the caecum and distal colon. No changes in proliferation were detected in lung, pancreas or gastric mucosa. The numbers of aberrant crypt foci in the mid-colon, distal colon and rectum following treatment with azoxymethane were also significantly increased by infusion with amidated or glycine-extended gastrin-releasing peptide. We conclude that administration of gastrin-releasing peptide to mature rats stimulates proliferation and accelerates carcinogenesis in the colorectal mucosa, and that C-terminal amidation is not essential for either effect. Gastrin-releasing peptides could thus potentially act as promoters of colorectal carcinogenesis.