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Human Melioidosis Caused by Novel Transmission of Burkholderia pseudomallei from Freshwater Home Aquarium, United States
Nearly all cases of melioidosis in the continental United States are related to international travel to areas to which Burkholderia pseudomallei, the bacterium that causes melioidosis, is endemic. We report the diagnosis and clinical course of melioidosis in a patient from the United States who had no international travel history and the public health investigation to determine the source of exposure. We tested environmental samples collected from the patient’s home for B. pseudomallei by PCR and culture. Whole-genome sequencing was conducted on PCR-positive environmental samples, and results were compared with sequences from the patient’s clinical specimen. Three PCR-positive environmental samples, all collected from a freshwater home aquarium that had contained imported tropical fish, were a genetic match to the clinical isolate from the patient. This finding suggests a novel route of exposure and a potential for importation of B. pseudomallei, a select agent, into the United States from disease-endemic areas.
Journal Article
The Mre11 Nuclease Is Critical for the Sensitivity of Cells to Chk1 Inhibition
The Chk1 kinase is required for the arrest of cell cycle progression when DNA is damaged, and for stabilizing stalled replication forks. As a consequence, many Chk1 inhibitors have been developed and tested for their potential to enhance DNA damage-induced tumor cell killing. However, inhibition of Chk1 alone, without any additional exogenous agent, can be cytotoxic. Understanding the underlying mechanisms of this sensitivity is critical for defining which patients might respond best to therapy with Chk1 inhibitors. We have investigated the mechanism of sensitivity in U2OS osteosarcoma cells. Upon incubation with the Chk1 inhibitor MK-8776, single-stranded DNA regions (ssDNA) and double-strand breaks (DSB) begin to appear within 6 h. These DSB have been attributed to the structure-specific DNA endonuclease, Mus81. The Mre11/Rad50/Nbs1 complex is known to be responsible for the resection of DSB to ssDNA. However, we show that inhibition of the Mre11 nuclease activity leads, not only to a decrease in the amount of ssDNA following Chk1 inhibition, but also inhibits the formation of DSB, suggesting that DSB are a consequence of ssDNA formation. These findings were corroborated by the discovery that Mre11-deficient ATLD1 cells are highly resistant to MK-8776 and form neither ssDNA nor DSB following treatment. However, once complimented with exogenous Mre11, the cells accumulate both ssDNA and DSB when incubated with MK-8776. Our findings suggest that Mre11 provides the link between aberrant activation of Cdc25A/Cdk2 and Mus81. The results highlight a novel role for Mre11 in the production of DSB and may help define which tumors are more sensitive to MK-8776 alone or in combination with DNA damaging agents.
Journal Article
Sensitization of human cancer cells to gemcitabine by the Chk1 inhibitor MK-8776: cell cycle perturbation and impact of administration schedule in vitro and in vivo
Background
Chk1 inhibitors have emerged as promising anticancer therapeutic agents particularly when combined with antimetabolites such as gemcitabine, cytarabine or hydroxyurea. Here, we address the importance of appropriate drug scheduling when gemcitabine is combined with the Chk1 inhibitor MK-8776, and the mechanisms involved in the schedule dependence.
Methods
Growth inhibition induced by gemcitabine plus MK-8776 was assessed across multiple cancer cell lines. Experiments used clinically relevant “bolus” administration of both drugs rather than continuous drug exposures. We assessed the effect of different treatment schedules on cell cycle perturbation and tumor cell growth in vitro and in xenograft tumor models.
Results
MK-8776 induced an average 7-fold sensitization to gemcitabine in 16 cancer cell lines. The time of MK-8776 administration significantly affected the response of tumor cells to gemcitabine. Although gemcitabine induced rapid cell cycle arrest, the stalled replication forks were not initially dependent on Chk1 for stability. By 18 h, RAD51 was loaded onto DNA indicative of homologous recombination. Inhibition of Chk1 at 18 h rapidly dissociated RAD51 leading to the collapse of replication forks and cell death. Addition of MK-8776 from 18–24 h after a 6-h incubation with gemcitabine induced much greater sensitization than if the two drugs were incubated concurrently for 6 h. The ability of this short incubation with MK-8776 to sensitize cells is critical because of the short half-life of MK-8776 in patients’ plasma. Cell cycle perturbation was also assessed in human pancreas tumor xenografts in mice. There was a dramatic accumulation of cells in S/G
2
phase 18 h after gemcitabine administration, but cells had started to recover by 42 h. Administration of MK-8776 18 h after gemcitabine caused significantly delayed tumor growth compared to either drug alone, or when the two drugs were administered with only a 30 min interval.
Conclusions
There are two reasons why delayed addition of MK-8776 enhances sensitivity to gemcitabine: first, there is an increased number of cells arrested in S phase; and second, the arrested cells have adequate time to initiate recombination and thereby become Chk1 dependent. These results have important implications for the design of clinical trials using this drug combination.
Journal Article
Human Melioidosis Caused by Novel Transmission of Burkholderia pseudomallei from Freshwater Home Aquarium, United States1
Nearly all cases of melioidosis in the continental United States are related to international travel to areas to which Burkholderia pseudomallei, the bacterium that causes melioidosis, is endemic. We report the diagnosis and clinical course of melioidosis in a patient from the United States who had no international travel history and the public health investigation to determine the source of exposure. We tested environmental samples collected from the patient's home for B. pseudomallei by PCR and culture. Whole-genome sequencing was conducted on PCR-positive environmental samples, and results were compared with sequences from the patient's clinical specimen. Three PCR-positive environmental samples, all collected from a freshwater home aquarium that had contained imported tropical fish, were a genetic match to the clinical isolate from the patient. This finding suggests a novel route of exposure and a potential for importation of B. pseudomallei, a select agent, into the United States from disease-endemic areas.Nearly all cases of melioidosis in the continental United States are related to international travel to areas to which Burkholderia pseudomallei, the bacterium that causes melioidosis, is endemic. We report the diagnosis and clinical course of melioidosis in a patient from the United States who had no international travel history and the public health investigation to determine the source of exposure. We tested environmental samples collected from the patient's home for B. pseudomallei by PCR and culture. Whole-genome sequencing was conducted on PCR-positive environmental samples, and results were compared with sequences from the patient's clinical specimen. Three PCR-positive environmental samples, all collected from a freshwater home aquarium that had contained imported tropical fish, were a genetic match to the clinical isolate from the patient. This finding suggests a novel route of exposure and a potential for importation of B. pseudomallei, a select agent, into the United States from disease-endemic areas.
Journal Article
ملك أوز الضائع /
رواية يلتقي فيها الشر والخير، ويضيع بين سطورها الملك، ويتعاون على مشاقهم الرفاق، لكنها تعلمنا بأن الإنسان قد يستفيد من إخفاقاته أكثر مما يستفيد من نجاحاته، وأن التعاون بين الناس ومساندة بعضهم بعضا قد يجعل الأمور العسيرة خفيفة لا يبتئس منها الواقع فيها، وأن الرفقة الطيبة هم عتاد الأيام وبهم يقدر الإنسان أن يتجاوز ما يمر به ويسترد ما خسره مهما كانت خسارته عظيمة : فهل يعود الملك الضائع، وكيف يعود، ومن يعيده ؟.
Book
Visualising the voices of nursing: a co-designed video capturing the lived experiences of nurses in Northern Ireland during the COVID-19 pandemic
Background
Nurses were at the forefront of managing the COVID-19 pandemic. In response, the Royal College of Nursing in Northern Ireland commissioned a longitudinal qualitative survey using the Cognitive Edge SenseMaker
®
tool to capture nurses’ experiences of delivering care from April 2020 to March 2021.
Aim
To explore the effect of a co-designed video based on the findings of SenseMaker
®
, of the lived experience of nurses in Northern Ireland during the 2020/2021 global pandemic.
Method
Quotes were selected from the SenseMaker
®
report of nurses’ (
n
= 676) which conveyed the experiences of nurses during COVID-19. Three co-design workshops were conducted. The first covering the plan for extraction of data from the SenseMaker
®
report, the second content development and script writing and the third covering feedback and revisions. The video was filmed and edited in the Drama Studies, School of Arts, English and Languages, Queen’s University Belfast. The live launch event took place in the Royal College of Nursing conference venue on 8th February 2024. Data to gauge the effect of the video were gathered via audience participation, MS Teams Version 1.7. chat participation, Mentimeter poll and MS forms survey. The link for the video and survey was accessible via the School of Nursing and Midwifery, Queens University Belfast website after the launch event. The findings were analysed using systematic text condensation using NVivo version 1.6. The study was approved by the Faculty of Medicine, Health and Life Sciences research committee at Queen’s University Belfast following peer review (REC Reference: MHLS 23_100).
Results
Twenty-eight participants completed the survey; 30 participants attended the live event. Overall, 93% (
n
= 26) of participants confirmed that the video-based monologues effectively conveyed the emotional perspective and lived experiences of nurses during the COVID-19 pandemic. Four themes emerged - personal reflection and emotional effect, connection and solidarity amidst disappointment, moral injury and resentment, lessons learned and the need for change.
Conclusion
Wider dissemination of the co-created video-based narratives, with focus on advocacy to policy makers, is needed to prioritise the emotional well-being of nurses and other professionals. There is potential in using video-based monologies to facilitate positive change and better support for professionals, including nursing students in future crises. Further research is needed to assess the broader effect of such healthcare-related research methodologies.
Journal Article