Substrate docking to γ-secretase allows access of γ-secretase modulators to an allosteric site

γ-Secretase generates the peptides of Alzheimer's disease, Aβ40 and Aβ42, by cleaving the amyloid precursor protein within its transmembrane domain. γ-Secretase also cleaves numerous other substrates, raising concerns about γ-secretase inhibitor off-target effects. Another important class of drugs, γ-secretase modulators, alter the cleavage site of γ-secretase on amyloid precursor protein, changing the Aβ42/Aβ40 ratio, and are thus a promising therapeutic approach for Alzheimer's disease. However, the target for γ-secretase modulators is uncertain, with some data suggesting that they function on γ-secretase, whereas others support their binding to the amyloid precursor. In this paper we address this controversy by using a fluorescence resonance energy transfer-based assay to examine whether γ-secretase modulators alter Presenilin-1/γ-secretase conformation in intact cells in the absence of its natural substrates such as amyloid precursor protein and Notch. We report that the γ-secretase allosteric site is located within the γ-secretase complex, but substrate docking is needed for γ-secretase modulators to access this site

A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: management strategies and economic impact

This systematic review aimed to assess the literature for management strategies and economic impact of salivary gland hypofunction and xerostomia induced by cancer therapies and to determine the quality of evidence-based management recommendations.The electronic databases of MEDLINE/PubMed and EMBASE were searched for articles published in English since the 1989 NIH Development Consensus Conference on the Oral Complications of Cancer Therapies until 2008 inclusive. for each article, two independent reviewers extracted information regarding study design, study population, interventions, outcome measures, results, and conclusions.Seventy-two interventional studies met the inclusion criteria. in addition, 49 intensity-modulated radiation therapy (IMRT) studies were included as a management strategy aiming for less salivary gland damage. Management guideline recommendations were drawn up for IMRT, amifostine, muscarinic agonist stimulation, oral mucosal lubricants, acupuncture, and submandibular gland transfer.There is evidence that salivary gland hypofunction and xerostomia induced by cancer therapies can be prevented or symptoms be minimized to some degree, depending on the type of cancer treatment. Management guideline recommendations are provided for IMRT, amifostine, muscarinic agonist stimulation, oral mucosal lubricants, acupuncture, and submandibular gland transfer. Fields of sparse literature identified included effects of gustatory and masticatory stimulation, specific oral mucosal lubricant formulas, submandibular gland transfer, acupuncture, hyperbaric oxygen treatment, management strategies in pediatric cancer populations, and the economic consequences of salivary gland hypofunction and xerostomia.Univ Copenhagen, Dept Oral Med Clin Oral Physiol Oral Pathol & Ana, Inst Odontol, Fac Hlth Sci, DK-2200 Copenhagen, DenmarkUniv Groningen, Dept Oral & Maxillofacial Surg, Univ Med Ctr Groningen, NL-9700 RB Groningen, NetherlandsHerlev Univ Hosp, Dept Oncol, DK-2730 Herlev, DenmarkUniv Delaware, Sch Nursing, Coll Hlth Sci, Newark, de 19716 USARoyal Marsden Hosp, Dept Palliat Med, Sutton SM2 5P5, Surrey, EnglandDutilh Inst Reabilitacao Facial Oral, Taquaral, BrazilIndiana Univ, Sch Nursing, Dept Adult Hlth, Indianapolis, in 46202 USAUniv Belgrade, Clin Periodontol & Oral Med, Fac Stomatol, Belgrade 11000, SerbiaUniversidade Federal de São Paulo, Serv Oral Med, IOP, Pediat Oncol Inst GRAACC, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Endocrinol, São Paulo, BrazilHosp Cancer Ctr Oeste Minas Gerais, IPOM, Dept Odontol,Inst Pesquisas Oncol Minas Gerais, Associacao Combate Cancer Ctr Oeste Minas Gerais, Minas Gerais, BrazilUniv Michigan, Dept Oral & Maxillofacial Surg, Hosp Dent, Sch Dent, Ann Arbor, MI 48109 USAGriffith Univ, Ctr Med & Oral Hlth, Gold Coast, Qld 4222, AustraliaCarolinas Med Ctr, Dept Oral Med, Charlotte, NC 28232 USAHosp Cancer Ctr Oeste Minas Gerais, Dept Oncol & Res, Associacao Combate Cancer Ctr Oeste Minas Gerais, Inst Pesquisas Oncol Minas Gerais,IPOM, Minas Gerais, BrazilHop Reg Sudbury Reg Hosp, Dept Dent, Sudbury Reg Hosp Canc Program, Sudbury, ON P3E 5J1, CanadaUniv Gothenburg, Dept Oral Immunol & Oral Med, Inst Odontol, Sahlgrenska Acad, S-41390 Gothenburg, SwedenUniv Maryland, Sch Dent, Dept Pathol & Diagnost Sci, Baltimore, MD 21201 USAGreenebaum Canc Ctr, Baltimore, MD 21201 USAUniv Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USAUniversidade Federal de São Paulo, Serv Oral Med, IOP, Pediat Oncol Inst GRAACC, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Endocrinol, São Paulo, BrazilWeb of Scienc

A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: prevalence, severity and impact on quality of life

This systematic review aimed to assess the literature for prevalence, severity, and impact on quality of life of salivary gland hypofunction and xerostomia induced by cancer therapies.The electronic databases of MEDLINE/PubMed and EMBASE were searched for articles published in English since the 1989 NIH Development Consensus Conference on the Oral Complications of Cancer Therapies until 2008 inclusive. Two independent reviewers extracted information regarding study design, study population, interventions, outcome measures, results and conclusions for each article.The inclusion criteria were met by 184 articles covering salivary gland hypofunction and xerostomia induced by conventional, 3D conformal radiotherapy or intensity-modulated radiotherapy in head and neck cancer patients, cancer chemotherapy, total body irradiation/hematopoietic stem cell transplantation, radioactive iodine treatment, and immunotherapy.Salivary gland hypofunction and xerostomia are induced by radiotherapy in the head and neck region depending on the cumulative radiation dose to the gland tissue. Treatment focus should be on optimized/new approaches to further reduce the dose to the parotids, and particularly submandibular and minor salivary glands, as these glands are major contributors to moistening of oral tissues. Other cancer treatments also induce salivary gland hypofunction, although to a lesser severity, and in the case of chemotherapy and immunotherapy, the adverse effect is temporary. Fields of sparse literature included pediatric cancer populations, cancer chemotherapy, radioactive iodine treatment, total body irradiation/hematopoietic stem cell transplantation, and immunotherapy.Univ Copenhagen, Dept Oral Med Clin Oral Physiol Oral Pathol & Ana, Inst Odontol, Fac Hlth Sci, DK-2200 Copenhagen, DenmarkUniv Groningen, Dept Oral & Maxillofacial Surg, Univ Med Ctr Groningen, NL-9700 RB Groningen, NetherlandsHerlev Univ Hosp, Dept Oncol, DK-2730 Herlev, DenmarkUniv Delaware, Sch Nursing, Coll Hlth Sci, Newark, de 19716 USARoyal Marsden Hosp, Dept Palliat Med, Sutton SM2 5P5, Surrey, EnglandDutilh Inst Reabilitacao Facial Oral, Taquaral, BrazilIndiana Univ, Dept Adult Hlth, Sch Nursing, Indianapolis, in 46202 USAUniv Belgrade, Clin Periodontol & Oral Med, Fac Stomatol, Belgrade 11000, SerbiaUniversidade Federal de São Paulo, Serv Oral Med, IOP Pediat Oncol Inst GRAACC, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Endocrinol, Med Paulista Sch, São Paulo, BrazilHosp Cancer Ctr Oeste Minas Gerais, Associacao Combate ao Cancer Ctr Oeste Minas Gera, Inst Pesquisas Oncol Minas Gerais, IPOM,Dept Odontol, Belo Horizonte, MG, BrazilUniv Michigan, Dept Oral & Maxillofacial Surg, Hosp Dent, Sch Dent, Ann Arbor, MI 48109 USAGriffith Univ, Ctr Med & Oral Hlth, Gold Coast, Qld 4222, AustraliaCarolinas Med Ctr, Dept Oral Med, Charlotte, NC 28232 USAUniv Gothenburg, Dept Oral Immunol & Oral Med, Inst Odontol, Sahlgrenska Acad, S-41390 Gothenburg, SwedenUniv Maryland, Dept Pathol & Diagnost Sci, Sch Dent, Baltimore, MD 21201 USAGreenebaum Canc Ctr, Baltimore, MD 21201 USAUniv Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USAUniversidade Federal de São Paulo, Serv Oral Med, IOP Pediat Oncol Inst GRAACC, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Endocrinol, Med Paulista Sch, São Paulo, BrazilWeb of Scienc