Zaed Z R Hamady

Publications (9)39.08 Total impact

• Source

  Available from: usda.gov

  Article: Treatment of colitis with a commensal gut bacterium engineered to secrete human TGF-β1 under the control of dietary xylan 1.

  Zaed Z R Hamady, Nigel Scott, Mark D Farrar, Meenu Wadhwa, Paula Dilger, Terence R Whitehead, Robin Thorpe, Keith T Holland, J Peter A Lodge, Simon R Carding
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  ABSTRACT: While cytokine therapy and the use of immunosuppressive cytokines such as transforming growth factor-β (TGF-β) offer great potential for the treatment of inflammatory bowel disease (IBD), issues concerning formulation, stability in vivo, delivery to target tissues, and potential toxicity need to be addressed. In consideration of these problems we engineered the human commensal bacterium Bacteroides ovatus for the controlled in situ delivery of TGF-β(1) and treatment of colitis. Sequence encoding the human tgf-β1 gene was cloned downstream of the xylanase promoter in the xylan operon of B. ovatus by homologous recombination. Resulting recombinants (BO-TGF) were tested for TGF-β production in the presence and absence of polysaccharide xylan in vitro and in vivo, and used to treat experimental murine colitis. Clinical and pathological scores were used to assess the effectiveness of therapy. Colonic inflammatory markers including inflammatory cytokine expression were assessed by colorimetric assay and real-time polymerase chain reaction (PCR). BO-TGF secreted high levels of biologically active dimeric TGF-β in vitro and in vivo in a xylan-controlled manner. Administration of xylan in drinking water to BO-TGF-treated mice resulted in a significant clinical improvement of colitis, accelerating healing of damaged colonic epithelium, reducing inflammatory cell infiltration, reducing expression of proinflammatory cytokines, and promoting production of mucin-rich goblet cells in colonic crypts. These beneficial effects are comparable and in most cases superior to that achieved by conventional steroid therapy. This novel drug delivery system has potential for the targeted and controlled delivery of TGF-β(1) and other immunotherapeutic agents for the long-term management of various bowel disorders.
  Inflammatory Bowel Diseases 09/2011; 17(9):1925-35. · 4.86 Impact Factor
• Article: Treatment of colitis with a commensal gut bacterium engineered to secrete human tgf‐β1 under the control of dietary xylan 1

  ChB Zaed Z.R. Hamady MB, ChB Nigel Scott MB, Mark D. Farrar PhD, Meenu Wadhwa PhD, Paula Dilger PhD, Terence R. Whitehead PhD, Robin Thorpe PhD, Keith T. Holland PhD, ChB J. Peter A. Lodge MB, Simon R. Carding PhD, Zaed Z.R. Hamady, Nigel Scott, Mark D. Farrar, Meenu Wadhwa, Paula Dilger, Terence R. Whitehead, Robin Thorpe, Keith T. Holland, J. Peter A. Lodge, Simon R. Carding
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  ABSTRACT: Background:While cytokine therapy and the use of immunosuppressive cytokines such as transforming growth factor-β (TGF-β) offer great potential for the treatment of inflammatory bowel disease (IBD), issues concerning formulation, stability in vivo, delivery to target tissues, and potential toxicity need to be addressed. In consideration of these problems we engineered the human commensal bacterium Bacteroidesovatus for the controlled in situ delivery of TGF-β1 and treatment of colitis.Methods:Sequence encoding the human tgf-β1 gene was cloned downstream of the xylanase promoter in the xylan operon of B.ovatus by homologous recombination. Resulting recombinants (BO-TGF) were tested for TGF-β production in the presence and absence of polysaccharide xylan in vitro and in vivo, and used to treat experimental murine colitis. Clinical and pathological scores were used to assess the effectiveness of therapy. Colonic inflammatory markers including inflammatory cytokine expression were assessed by colorimetric assay and real-time polymerase chain reaction (PCR).Results:BO-TGF secreted high levels of biologically active dimeric TGF-β in vitro and in vivo in a xylan-controlled manner. Administration of xylan in drinking water to BO-TGF-treated mice resulted in a significant clinical improvement of colitis, accelerating healing of damaged colonic epithelium, reducing inflammatory cell infiltration, reducing expression of proinflammatory cytokines, and promoting production of mucin-rich goblet cells in colonic crypts. These beneficial effects are comparable and in most cases superior to that achieved by conventional steroid therapy.Conclusions:This novel drug delivery system has potential for the targeted and controlled delivery of TGF-β1 and other immunotherapeutic agents for the long-term management of various bowel disorders. (Inflamm Bowel Dis 2010;)
  Inflammatory Bowel Diseases 08/2011; 17(9):1925 - 1935. · 4.86 Impact Factor
• Article: SACN iron recommendations. Pregnancy is a special case.

  Nisreen A Alwan, Zaed Z R Hamady, Janet E Cade
  BMJ (Clinical research ed.). 01/2011; 342:d1783.
• Article: Pregnancy is a special case

  Nisreen A Alwan, Zaed Z R Hamady, Janet E Cade
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  ABSTRACT: The recent Scientific Advisory Committee on Nutrition (SACN) report recommends reducing red and processed meat consumption to 70 mg/day because of links with colorectal cancer.1 2 This recommendation is largely based on evidence from prospective studies in middle aged and elderly participants.Around 25% of women of reproductive age in Western societies have iron deficiency anaemia,3 which during early pregnancy increases the risk of preterm birth, low birth weight, infant mortality, and iron deficiency.4 Around 41% of women under 34 years have dietary iron intakes less than the lower reference nutrient intake of 8 mg/day according to the national diet and nutrition survey in Great Britain, and this was true of one in four women in our study of around 1300 pregnant women in Leeds.5The National Institute for Health and Clinical Excellence antenatal guidelines recommend investigating haemoglobin <110 g/L in the first trimester or 105 g/L at 28 weeks and considering iron supplementation. The problem arises when supplements are abandoned because of common side effects such as nausea and constipation. Current UK antenatal care does not provide specific dietary advice in relation to iron intake during pregnancy. Recommending meat as the source of the readily absorbed haem iron during the limited span of pregnancy is unlikely to have adverse effects in relation to lifetime risk of colorectal cancer. A public health approach towards increasing dietary iron intake and optimising iron absorption from non-haem sources, whether from diet or supplements, during pregnancy is needed.We recommend considering iron intake during pregnancy separately from lifelong recommendations for red meat intake.NotesCite this as: BMJ 2011;342:d1783FootnotesCompeting interests: None declared.References↵News. In brief. BMJ2011;342:d1338. (1 March.) OpenUrlFREE Full Text↵Scientific Advisory Committee on Nutrition (SACN). Iron and health. 2011. www.sacn.gov.uk/reports_position_statements/reports/sacn_iron_and_health_report.html. ↵Milman N. Prepartum anaemia: prevention and treatment. Ann Hematol2008;87:949-59.OpenUrlCrossRefMedlineWeb of Science↵Zimmermann MB, Hurrell RF. Nutritional iron deficiency. Lancet2007;370:511-20. OpenUrlCrossRefMedlineWeb of Science↵Alwan NA, Greenwood DC, Simpson NA, McArdle HJ, Godfrey KM, Cade JE. Dietary iron intake during early pregnancy and birth outcomes in a cohort of British women. Hum Reprod2011;26:911-9. OpenUrlFREE Full Text
  BMJ. 12/2010; 342.
• Source

  Available from: narod.ru

  Article: Xylan-regulated delivery of human keratinocyte growth factor-2 to the inflamed colon by the human anaerobic commensal bacterium Bacteroides ovatus.

  Zaed Z R Hamady, Nigel Scott, Mark D Farrar, J Peter A Lodge, Keith T Holland, Terence Whitehead, Simon R Carding
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  ABSTRACT: Human growth factors are potential therapeutic agents for various inflammatory disorders affecting the gastrointestinal tract. However, they are unstable when administered orally and systemic administration requires high doses increasing the risk of unwanted side effects. Live microorganism-based delivery systems can overcome these problems although they suffer from the inability to control heterologous protein production and there are concerns regarding biosafety and environmental contamination. To overcome these limitations we have developed a new live bacteria drug-delivery system using the human commensal gut bacterium Bacteroides ovatus engineered to secrete human growth factors in response to dietary xylan. The anaerobic nature of B ovatus provides an inherent biosafety feature. B ovatus strains expressing human keratinocyte growth factor-2, which plays a central role in intestinal epithelial homeostasis and repair (BO-KGF), were generated by homologous recombination and evaluated using the dextran sodium sulfate (DSS)-induced model of intestinal epithelial injury and colitis. In response to xylan BO-KGF produced biologically active KGF both in vitro and in vivo. In DSS treated mice administration of xylan and BO-KGF had a significant therapeutic effect in reducing weight loss, improving stool consistency, reducing rectal bleeding, accelerating healing of damaged epithelium, reducing inflammation and neutrophil infiltration, reducing expression of pro-inflammatory cytokines, and accelerating production of goblet cells. BO-KGF and xylan treatment also had a marked prophylactic effect limiting the development of inflammation and disruption of the epithelial barrier. This novel, diet-regulated, live bacterial drug delivery system may be applicable to treating various bowel disorders.
  Gut 10/2009; 59(4):461-9. · 10.11 Impact Factor
• Article: Identification and use of the putative Bacteroides ovatus xylanase promoter for the inducible production of recombinant human proteins.

  Zaed Z R Hamady, Mark D Farrar, Terence R Whitehead, Keith T Holland, J Peter A Lodge, Simon R Carding
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  ABSTRACT: The use of genetically modified bacteria to deliver biologically active molecules directly to the gut has become an increasingly attractive area of investigation. The challenge of regulation of production of the therapeutic molecule and colonization of the bowel led us to investigate Bacteroides ovatus for the production of these molecules, due to its ability to colonize the colon and xylan utilization properties. Here we have identified the putative xylanase promoter. The 5' region of the corresponding mRNA was determined by 5'RACE analysis and the transcription initiation site was identified 216 bp upstream of the ATG start codon. The putative xylanase promoter was regulated by xylan in a dose- and time-dependent manner, and repressed by glucose. This promoter was subsequently used to direct the controlled expression of a gene encoding the human intestinal trefoil factor (TFF-3) after integration as a single copy into the chromosome of B. ovatus. The resulting strain produced biologically active TFF-3 in the presence of xylan. These findings identify the B. ovatus xylanase operon promoter and show that it can be utilized to direct xylan-inducible expression of heterologous eukaryotic genes in B. ovatus.
  Microbiology 11/2008; 154(Pt 10):3165-74. · 3.06 Impact Factor
• Article: Hepatic resection for colorectal metastasis: impact of tumour size.

  Zaed Z R Hamady, Hassan Z Malik, Robert Finch, Robert Adair, Ahmad Al-Mukhtar, K Rajendra Prasad, Giles J Toogood, J Peter A Lodge
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  ABSTRACT: Many colorectal liver metastasis patients are denied surgical resection on the basis of tumour size. The aim of this study was to explore the impact of metastasis size on modern liver resection. Using a prospectively collected database, this was a retrospective analysis of 484 consecutive patients who underwent liver resection for colorectal liver metastases between 1993 and 2003. The cohort was divided into two groups: smaller metastases (< 8 cm) and larger metastases (> or = 8 cm). Those with larger metastases were then further stratified into big metastases (8-12 cm) and giant metastases (> 12 cm). Demographic, pathological, surgical technique and outcome data were compared between the groups. There were 88 (18%) patients with metastases measuring 8 cm or larger. There was an association between higher carcinoembryonic antigen (CEA) and cancer antigen (CA) 19-9 levels and larger metastases. The actuarial 5-year survival for patients with larger metastases was 38% compared with 42% for smaller metastases (not statistically significant). Patients with giant metastases had poorer overall and disease-free survival (both nonsignificant) compared with those with big metastases: 29% and 28% at 5 years, respectively. Patients with colorectal liver metastasis greater than 8 cm and up to 12 cm in size should not be treated differently from those with smaller lesions.
  Annals of Surgical Oncology 11/2006; 13(11):1493-9. · 4.17 Impact Factor
• Article: Left hepatic trisectionectomy for hepatobiliary malignancy: results and an appraisal of its current role.

  Hideki Nishio, Ernest Hidalgo, Zaed Z R Hamady, Kadiyala V Ravindra, Anil Kotru, Dowmitra Dasgupta, Ahmed Al-Mukhtar, K Rajendra Prasad, Giles J Toogood, J Peter A Lodge
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  ABSTRACT: To analyze results of 70 patients undergoing left hepatic trisectionectomy and to clarify its current role. Left hepatic trisectionectomy remains a complicated hepatectomy, and few reports have described the long-term results of the procedure. Short-term and long-term outcomes of 70 consecutive patients who underwent left hepatic trisectionectomy from January 1993 to February 2004 were analyzed. Of the 70 patients, 36 had colorectal liver metastasis, 24 had cholangiocarcinoma, 4 had hepatocellular carcinoma, and the remaining 6 had other tumors. Overall morbidity, 30-day and 90-day mortality rates were 46%, 7%, and 9%, respectively. Multivariate analysis disclosed that preoperative jaundice and intraoperative blood transfusion were positive independent predictors for postoperative morbidity; however, there were no independent predictors for postoperative mortality. Postoperative morbidity (87% versus 35%, P < 0.001) and mortality (20% versus 5%, P = 0.108) were observed more frequently in patients with preoperative obstructive jaundice than in those without jaundice. Each survival according to tumor type was acceptable compared with reported survivals. Survival for patients with colorectal liver metastasis undergoing left hepatic trisectionectomy with concomitant partial resection of the remnant liver was similar to those without this concomitant procedure. This concomitant procedure was not associated with postoperative morbidity and mortality. Left hepatic trisectionectomy remains a challenging procedure. Preoperative obstructive jaundice considerably increases perioperative risk. Concomitant partial resection of the remaining liver appears to be safe and offers the potential for cure in patients with colorectal metastasis affecting all liver segments.
  Annals of Surgery 08/2005; 242(2):267-75. · 7.49 Impact Factor
• Article: Current techniques and results of liver resection for colorectal liver metastases.

  Zaed Z R Hamady, Anil Kotru, Hideki Nishio, J Peter A Lodge
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  ABSTRACT: Colorectal cancer remains the second most common cause of cancer death in the West. Every year in the UK alone, around 14 000 patients develop secondary hepatic deposits from a primary colorectal cancer. Surgery remains the mainstay of treatment for liver metastases. Although not every patient is a candidate for surgery, earlier referral and rapid assessment are required to improve outcome. With the use of most recent technologies and radical surgery, increasing numbers of patients should have therapy with curative intent. This paper reviews preoperative patient evaluation and selection, surgical strategies, adjuvant therapy and postoperative follow-up. Other treatment modalities to increase tumour resectability are also described.
  British Medical Bulletin 02/2004; 70:87-104. · 4.54 Impact Factor