肺胞マクロファージにおけるneuropilinの特異的発現

学位論文要約山形大

530 A first-in-human phase I study of M6223 (TIGIT inhibitor) as monotherapy or in combination with bintrafusp alfa in patients with metastatic or locally advanced solid unresectable tumors

BackgroundT cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) is an inhibitory receptor expressed on T cells, including regulatory T cells (Tregs) and natural killer (NK) cells. In the tumor microenvironment, TIGIT is often overexpressed and directly inhibits both T cell and NK cell effector function and proliferation. TIGIT is also involved in regulating Treg function. Therefore, inhibiting the TIGIT-related immunosuppressive pathway may result in antitumor activity. M6223 is an intravenously (IV) administered, human, antagonistic, immunoglobulin G1 (IgG1) anti-TIGIT antibody with an Fc mediated effector region. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the human transforming growth factor β receptor II (a TGFβ "trap") fused to a human IgG1 monoclonal antibody blocking programed death ligand 1 (PD-L1). As TIGIT and programed death receptor 1 (PD-1) are co-expressed on T cells, dual inhibition of both immune checkpoints may enhance antitumor activity. This phase Ia study (NCT04457778) aims to determine the safety, tolerability, maximum tolerated dose and recommended dose for expansion of M6223 monotherapy and M6223 (both the once every 2 weeks [Q2W] and once every 3 weeks [Q3W] regimens) in combination with bintrafusp alfa. Secondary objectives include the evaluation of pharmacokinetics and clinical activity of M6223 with and without bintrafusp alfa.MethodsEligible patients include those aged ≥18 years with: an Eastern Cooperative Oncology Group performance status ≤1; adequate baseline hematological, renal and hepatic function; and histologically or cytologically proven locally advanced or advanced solid tumors, for which no effective standard therapy is available. Patients previously treated with a TIGIT targeting agent or bintrafusp alfa are excluded. Patients with brain metastases are also excluded, except those without neurological symptoms ≥4 weeks before start of treatment and those receiving either a stable or decreasing dose of steroids <10 mg/day or no steroid treatment.In the monotherapy dose escalation phase, approximately 17–26 patients will receive M6223 IV at one of the six dose levels planned (10–1600 mg Q2W). In the combination dose escalation phase, 18–21 patients will receive M6223 IV at one of four dose levels planned (300, 900, 1600 mg Q2W and 2400 mg Q3W) in combination with bintrafusp alfa IV (1200 mg Q2W or 2400 mg Q3W). Dose escalation is determined by the safety monitoring committee and supported by a Bayesian 2-parameter logistic regression model. The study is currently ongoing in the United States and Canada.AcknowledgementsThe authors would like to thank Daniel Holland of the healthcare business of Merck KGaA, Darmstadt, Germany for his involvement and contribution to the design and conduct of this study. Medical writing assistance was provided by David Lester of Bioscript Stirling Ltd, Macclesfield, UK, and funded by the healthcare business of Merck KGaA, Darmstadt, Germany [CrossRef Funder ID: 10.13039/100009945].Funding: The healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945).Trial RegistrationNCT04457778Ethics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site. All patients provided written informed consent before any study procedures were performed

Tumor Content Is Not Linked To Pembrolizumab Response In Rare Tumors

https://openworks.mdanderson.org/sumexp23/1079/thumbnail.jp

Development of Leucaena Mimosine-Degrading Bacteria in the Rumen of Sheep in Myanmar

Myanmar has an agricultural base, and about 70% of people reside in rural areas. They depend for survival on agriculture and small-scale crop production, with ruminant livestock consuming fibrous agricultural residues. For optimal ruminant production, concentrates are needed as supplements to these residues. As concentrates are expensive, researchers are testing alternative protein sources like legumes, including foliage from leguminous trees such as leucaena (Leucaena leucocephala). Leucaena is the most widely used leguminous tree as a ruminant feed because it is rich in protein (~ 22%) and contains easily digestible fibre (23% neutral detergent fibre, 16.6% acid detergent fibre; Ni Ni Maw 2004). Khin Htay Myint (2005) noted that 25% of leucaena in the ration tended to increase nitrogen retention without decreasing dry matter and organic matter digestibilities. However, leucaena leaves contain a toxic non-protein amino acid, called mimosine. Research workers have endeavoured to reduce mimosine toxicity in animals fed leucaena in Myanmar (Aung Aung 2007, Wink Phyo Thu 2010) and one avenue of research was the development of mimosine-degrading bacteria in the rumen of sheep fed leucaena. In this paper we describe an experiment tracing the development of mimosine-degrading bacteria in the rumen of sheep

Design, construction and testing of an I-V tester for thin-film solar cells and mini-modules

Master'sMASTER OF ENGINEERIN

Toll-like receptor 9 and 4 gene polymorphisms in susceptibility and severity of malaria: a meta-analysis of genetic association studies

Background: Malaria is still a major public health problem in sub-Saharan Africa and South-east Asia. The clinical presentations of malaria infection vary from a mild febrile illness to life-threatening severe malaria. Toll like receptors (TLRs) are postulated to be involved in the innate immune responses to malaria. Individual studies showed inconclusive findings. This study aimed to assess the role of TLR4 (D299G, T399I) and TLR9 (T1237C, T1486C) in severity or susceptibility of malaria by meta-analysis of data from eligible studies. Methods: Relevant case–control studies that assessed the association between TLR 4/9 and malaria either in susceptibility or progression were searched in health-related electronic databases. Quality of included studies was evaluated with Newcastle–Ottawa scale. Pooled analyses for specific genetic polymorphisms were done under five genetic models. Stratified analysis was done by age and geographical region (Asian countries vs non-Asian countries). Results: Eleven studies (2716 cases and 2376 controls) from nine endemic countries were identified. Five studies (45.4%) obtained high score in quality assessment. Overall, a significant association between TLR9 (T1486C) and severity of malaria is observed in allele model (OR: 1.26, 95% CI: 1.08–1.48, I2 = 0%) or homozygous model (OR: 1.55, 95% CI: 1.08–2.28, I2 = 0%). For TLR9 (T1237C), a significant association with severity of malaria is observed in in heterozygous model (OR:1.89, 95% CI: 1.11–3.22, I2 = 75%). On stratifications, TLR9 (T1486C) is only significantly associated with a subgroup of children of non-Asian countries under allele model (OR: 1.25, 95% CI: 1.02–1.38), while 1237 is with a subgroup of adults from Asian countries under heterozygous model (OR: 2.0, 95% CI: 1.09–3.64, I2 = 39%). Regarding the susceptibility to malaria, TLR9 (T1237C) is significantly associated only with the children group under recessive model (OR: 2.21, 95% CI: 1.06–4.57, I2=85%) and homozygous model (OR: 1.49, 95% CI: 1.09–2.0, I2 = 0%). For TLR4 (D299G, T399I), none is significantly associated with either severity of malaria or susceptibility to malaria under any genetic models. Conclusions: The findings suggest that TLR 9 (T1486C and T1237C) seems to influence the progression of malaria, under certain genetic models and in specific age group of people from specific geographical region. TLR 9 (T1237C) also plays a role in susceptibility to malaria under certain genetic models and only with children of non-Asian countries. To substantiate these, future well designed studies with larger samples across endemic countries are needed

Tamoxifen for hepatocellular carcinoma

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows:. To assess the benefits and harms of tamoxifen in people with hepatocellular carcinoma, irrespective of sex, administered dose, type of formulation, and duration of treatment

A pilot study of temsirolimus and body composition.

PurposeBody weight and composition play a role in cancer etiology, prognosis, and treatment response. Therefore, we analyzed the weight, body composition changes, and outcome in patients treated with temsirolimus, an mTor inhibitor that has weight loss as one of its side effects.Patients and methodsSixteen patients with advanced solid tumors treated with temsirolimus were studied; body composition was evaluated utilizing computerized tomography images. Sarcopenia was defined as skeletal muscle index lower than 38.5 cm(2)/m(2) for women and 52.4 cm(2)/m(2) for men.ResultsFive of 16 patients (31 %) were men; median age, 60 years. Forty-four percent (7/16) of patients were sarcopenic. Fatigue, anemia, hyperglycemia, and hyperlipidemia were common. Baseline sarcopenia and body composition did not correlate with worse toxicity or treatment outcome. However, there was a trend for greater loss of adipose area (p = 0.07), fat mass (p = 0.09), and adipose index (p = 0.07) for patients with grade 3 or 4 toxicities versus those with grade 1 and 2 side effects.ConclusionPatients with higher grade toxicities tended to lose more body fat, suggesting a possible end-organ metabolic effect of temsirolimus. These observations merit exploration in a larger cohort of patients