Is extensive surgery warranted in the management of hilar tuberculosis? A lesson learned

Maymona CHOUDRY,Jonathan NAVARRO,Theo Genesis TAGAYTAY 한국간담췌외과학회 2022 Annals of hepato-biliary-pancreatic surgery Vol.26 No.-

Hypoxia Promotes Synergy between Mitomycin C and Bortezomib through a Coordinated Process of Bcl-xL Phosphorylation and Mitochondrial Translocation of p53

Song, Xinxin,Dilly, Ashok-Kumar,Choudry, Haroon Asif,Bartlett, David L.,Kwon, Yong Tae,Lee, Yong J. American Association for Cancer Research 2015 Molecular Cancer Research Vol.13 No.12

<P>Colorectal peritoneal carcinomatosis (CPC) exhibits severe tumor hypoxia, leading to drug resistance and disease aggressiveness. This study demonstrates that the combination of the chemotherapeutic agent mitomycin C with the proteasome inhibitor bortezomib induced synergistic cytotoxicity and apoptosis, which was even more effective under hypoxia in colorectal cancer cells. The combination of mitomycin C and bortezomib at sublethal doses induced activation of c-Jun NH<SUB>2</SUB>-terminal kinase and p38 mitogen-activated protein kinase and resulted in Bcl-xL phosphorylation at Serine 62, leading to dissociation of Bcl-xL from proapoptotic Bak. Interestingly, the intracellular level of p53 became elevated and p53 translocated to the mitochondria during the combinatorial treatment, in particular under hypoxia. The coordinated action of Bcl-xL phosphorylation and p53 translocation to the mitochondria resulted in conformational activation of Bak oligomerization, facilitating cytochrome <I>c</I> release and apoptosis induction. In addition, the combinatorial treatment with mitomycin C and bortezomib significantly inhibited intraperitoneal tumor growth in LS174T cells and increased apoptosis, especially under hypoxic conditions <I>in vivo</I>. This study provides a preclinical rationale for the use of combination therapies for CPC patients.</P><P><B>Implications:</B> The combination of a chemotherapy agent and proteasome inhibitor at sublethal doses induced synergistic apoptosis, in particular under hypoxia, <I>in vitro</I> and <I>in vivo</I> through coordinated action of Bcl-xL and p53 on Bak activation. <I>Mol Cancer Res; 13(12); 1533–43. ©2015 AACR</I>.</P>

Follow-up of Metal-on-Metal Hip Replacements at a Large District Hospital and the Implementation of Medicines and Healthcare Products Regulatory Agency Guidelines: A Review of 297 Patients

Luke Hughes,Kathryn Chamberlain,Heather Robinson,Andrew Sloan,Qaisar Choudry 대한정형외과학회 2019 Clinics in Orthopedic Surgery Vol.11 No.4

Background: Medicines and Healthcare products Regulatory Agency (MHRA) guidance for patients with metal-on-metal (MoM) hip replacements was provided in 2012 and updated in 2017 to assist in the early detection of soft-tissue reactions due to metal wear debris. A large number of MoM hip replacements were undertaken at our hospital trust. A program of recall for all patients with MoM hip replacements was undertaken and MHRA guidelines were implemented. In this study, we aimed to investigate the effectiveness of the revised MHRA guidelines in the detection of early adverse reactions to metal debris and to re-evaluate the indications for metal artifact reduction sequence magnetic resonance imaging (MARS-MRI) and revision surgery. Methods: Identification and recall of all patients with MoM hip replacements from 2001 were conducted by using theatre logs, patient records, clinical coding information, and consultant logbooks. Two senior arthroplasty consultants reviewed X-rays and patient records. Postal questionnaires were forwarded to patients, together with requests for general practitioners to complete cobalt and chromium blood tests. The two consultant-led review of MOM replacements was undertaken with further radiological investigations (X-rays, MARS-MRI) performed according to the 2017 guidance with support of consultant radiologists. Results: Of 674 identified patients, 297 were available for review: 26 patients did not have MoM implants, 36 were untraceable, 59 refused follow-up, 87 moved out of area, 147 had died, and 22 already had revision. Of 297 patients, 126 were women and 171 were men; age range was 39 to 95 years (mean age, 69 years); 126 had resurfacing and 171 had MoM replacements. Twenty-six patients had elevated metal ions. Thirty-three patients underwent MARS-MRI: MARS-MRI results were positive in 17 and negative in 16. Of 17 patients with positive MARS-MRI, 10 patients were asymptomatic and seven were waiting revision. Conclusions: Positive MARS-MRI can often occur in the absence of elevated metal ion levels; elevated blood metal ion levels do not mean MARS-MRI will be positive. All patients with MoM replacements were at risk. It is imperative to assess patients regularly for symptoms that may raise clinical suspicion and maintain a low threshold to performing MARS-MRI.

Crosstalk Between Apoptosis and Autophagy Is Regulated by the Arginylated BiP/Beclin-1/p62 Complex

Song, Xinxin,Lee, Dae-Hee,Dilly, Ashok-Kumar,Lee, Young-Sun,Choudry, Haroon Asif,Kwon, Yong Tae,Bartlett, David L.,Lee, Yong J. American Association for Cancer Research 2018 Molecular Cancer Research Vol.16 No.7

<P>Emerging evidence demonstrates that autophagy and apoptosis are interconnected and their interplay greatly affects cell death. However, the key regulators in this crosstalk remain elusive. Therefore, the role of N-terminal arginylated BiP (R-BiP)/Beclin-1/p62 complex was examined in the crosstalk between apoptosis and autophagy during combination chemotherapy with mitomycin C and bortezomib using immunoblot, immunoprecipitation, and cellular imaging assays in wild-type (WT) and genetically engineered colorectal cancer cells. In addition, the tumoricidal efficacy of the combinatorial treatment in a nude mouse tumor xenograft model of colorectal cancer was assessed. Bortezomib combined with mitomycin C synergistically induced cytotoxicity and apoptosis rather than autophagy. Mechanistically, this combination inactivated Akt and subsequently induced Beclin-1 (<I>BECN1</I>) dephosphorylation at Ser 234/295. Dephosphorylation of Beclin-1 resulted in increased cleavage of Beclin-1 and disruption of the R-BiP/Beclin-1/p62 complex, which led to switching autophagy to the synergistic induction of apoptosis. Importantly, the combination significantly suppressed LS174T intraperitoneal xenograft tumor growth, induced Akt inactivation and Beclin-1 cleavage, and decreased autophagy <I>in vivo</I>. Moreover, the tumoricidal efficacy of the combinatorial treatment was less effective, <I>in vitro</I> and <I>in vivo</I>, in HCT116 tumors harboring a Beclin-1 caspase 8 cleavage site mutant knock-in.</P><P><B>Implications:</B> This study uncovers that the R-BiP/Beclin-1/p62 complex has an important role in the crosstalk between apoptosis and autophagy. The results also propose how mono-drug resistance can be overcome using potent combinations to improve anticancer therapy. <I>Mol Cancer Res; 16(7); 1077–91. ©2018 AACR</I>.</P>

Understanding the Adoption, Use and Diffusion of e-Services in Abu Dhabi Police Force: A Development Perspective

Jyoti Choudrie,Hassan Al-Zaabi 국제개발협력학회 2015 국제개발협력연구 Vol.7 No.1

Information and Communication Technologies (ICTs) are becoming increasingly prevalent in peoples’ daily lives due to the development and e-government initiatives. This research paper aims to identify and understand factors affecting the diffusion, adoption and use of e-services in a public sector organisation, in this case, Abu Dhabi Police Force (ADPF) in the United Arab Emirates (UAE). A qualitative approach involving 200 participants’ interviews was used in this study. The questions used in the interviews were based on a conceptual framework that applied certain constructs taken from Diffusion of Innovations Theory (DOI), Technology Acceptance Model (TAM) and e-Commerce’s Trustworthiness models. The research study results displayed that age, education, position within an organisation and job that an individual is involved with inhibit or encourage the use and adoption of e-services. The contributions from this research are anticipated to be a better understanding of the diffusion, adoption and use of e-services in the UAE region. For industry the findings offer a diverse perspective as they provide some information on the impacts of demographics in public sector organisations, something minimal in e-government and e-services research. Policymakers, particularly in the UAE and developing countries can learn of departments and personnel demographics where their efforts can obtain more success than others.