Natural killer (NK) cell survival and, hence, cytotoxicity requires cytokine support. We determined whether expression of interleukin-15 (IL-15) in a nonsecretory, membrane-bound form could sustain ...NK cell growth. We linked the human IL15 gene to that encoding CD8α transmembrane domain (mbIL15). After retroviral transduction, human NK cells expressed mbIL15 on the cell surface; IL-15 secretion was negligible. Survival of mbIL15-NK cells without interleukin-2 (IL-2) after 7-day culture was vastly superior to that of mock-transduced NK cells (P < .001, n = 15) and of NK cells expressing nonmembrane-bound IL-15 (P = .025, n = 9); viable mbIL15-NK cells were detectable for up to 2 months. In immunodeficient mice, mbIL15-NK cells expanded without IL-2 and were detectable in all tissues examined (except brain) in much higher numbers than mock-transduced NK cells (P < .001). Expansion further increased with IL-2. The primary mechanism of mbIL15 stimulation was autocrine; it activated IL-15 signaling and antiapoptotic signaling. NK cells expressing mbIL15 had higher cytotoxicity against leukemia, lymphoma, and solid tumor cells in vitro and against leukemia and sarcoma cells in xenograft models. Thus, mbIL15 confers independent growth to NK cells and enhances their antitumor capacity. Infusion of mbIL15-NK cells would allow NK cell therapy without the potential adverse effects of cytokine administration.
•Expression of IL-15 in a membrane-bound form sustains NK cell survival and expansion in vitro and in vivo without exogenous cytokines.•These NK cells have superior cytotoxicity against leukemia, lymphoma, and solid tumor cells, supporting their clinical testing.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
Background: Women with a history of gestational diabetes mellitus (GDM) have a 7-fold increased risk for subsequent development of type 2 diabetes mellitus (T2DM). Continuous glucose monitoring ...systems (CGMS) and exercise trackers have not been thoroughly explored in any Asian postpartum diabetes prevention studies. Objective: The Integrated Hyperglycaemia Incentivised Postnatal Surveillance (I-HIPS) study aims to investigate the efficacy of a personalized lifestyle intervention programme using wearables along with physical activity (PA) and diet modification to achieve healthy weight loss in postpartum women with history of GDM.
Methods: Women were randomized to receive the intervention or standard medical care. The intervention group received a CGM sensor and exercise tracker, along with nutrition, exercise and personalized goal-setting workshops. Anthropometric measures (weight, BMI and waist circumference (WC)) and PA assessed using the International Physical Activity Questionnaire were examined between the two arms at the 6-month follow-up. Changes in dietary behaviors in the intervention group were assessed using a validated 6P tool.
Results: Twenty-six recruited women had completed the 6-month follow-up. At 6-month, compared with the controls, women receiving intervention achieved a mean difference in the reduction of weight by 0.5 kg, BMI by 0.2 kg/m2 and WC by 0.8cm (p>0.05). The intervention group had increased PA (mean difference: +990 MET mins/week), compared to the controls (mean difference: +298 MET mins/week) (p>0.05) at 6-month. Between baseline and 6-month, women in the intervention group showed a reduction in the frequency of snack and beverage intakes (p=0.01).
Conclusion: Preliminary findings suggest a trend toward better health outcomes in the intervention group with improved dietary behaviour.
Disclosure
P.Quah: None. N.Razali: None. S.M.H.Chai: None. F.Fadzully: None. L.W.K.Ryan: None. C.Ku: None. S.Loy: None. K.Tan: None.
Funding
National Medical Research Council of Singapore (MOH-000504-03)
Cutaneous sclerosis occurs in 20% of patients with chronic graft-versus-host disease (GVHD) and can compromise mobility and quality of life.
We conducted a prospective, multicenter, randomized, ...two-arm phase II crossover trial of imatinib (200 mg daily) or rituximab (375 mg/m(2) i.v. weekly × 4 doses, repeatable after 3 months) for treatment of cutaneous sclerosis diagnosed within 18 months (NCT01309997). The primary endpoint was significant clinical response (SCR) at 6 months, defined as quantitative improvement in skin sclerosis or joint range of motion. Treatment success was defined as SCR at 6 months without crossover, recurrent malignancy or death. Secondary endpoints included changes of B-cell profiles in blood (BAFF levels and cellular subsets), patient-reported outcomes, and histopathology between responders and nonresponders with each therapy.
SCR was observed in 9 of 35 26%; 95% confidence interval (CI); 13%-43% participants randomized to imatinib and 10 of 37 (27%; 95% CI, 14%-44%) randomized to rituximab. Six (17%; 95% CI, 7%-34%) patients in the imatinib arm and 5 (14%; 95% CI, 5%-29%) in the rituximab arm had treatment success. Higher percentages of activated B cells (CD27(+)) were seen at enrollment in rituximab-treated patients who had treatment success (P = 0.01), but not in imatinib-treated patients.
These results support the need for more effective therapies for cutaneous sclerosis and suggest that activated B cells define a subgroup of patients with cutaneous sclerosis who are more likely to respond to rituximab.
Late acute (LA) graft-versus-host disease (GVHD) is persistent, recurrent, or new-onset acute GVHD symptoms occurring >100 days after allogeneic hematopoietic cell transplantation (HCT). The aim of ...this analysis is to describe the onset, course, morbidity, and mortality of and examine angiogenic factors associated with LA GVHD. A prospective cohort of patients (n = 909) was enrolled as part of an observational study within the Chronic GVHD Consortium. Eighty-three patients (11%) developed LA GVHD at a median of 160 (interquartile range, 128-204) days after HCT. Although 51 out of 83 (61%) achieved complete or partial response to initial therapy by 28 days, median failure-free survival was only 7.1 months (95% confidence interval, 3.4-19.1 months), and estimated overall survival (OS) at 2 years was 56%. Given recently described alterations of circulating angiogenic factors in classic acute GVHD, we examined whether alterations in such factors could be identified in LA GVHD. We first tested cases (n = 55) and controls (n = 50) from the Chronic GVHD Consortium and then validated the findings in 37 cases from Mount Sinai Acute GVHD International Consortium. Plasma amphiregulin (AREG; an epidermal growth factor EGF receptor ligand) was elevated, and an AREG/EGF ratio at or above the median was associated with inferior OS and increased nonrelapse mortality in both cohorts. Elevation of AREG was detected in classic acute GVHD, but not chronic GVHD. These prospective data characterize the clinical course of LA GVHD and demonstrate alterations in angiogenic factors that make LA GVHD biologically distinct from chronic GVHD.
•Under current treatment approaches, patients with LA GVHD have poor overall and failure-free survival.•Levels of AREG are elevated in LA GVHD, and the AREG/EGF ratio is predictive of overall survival and nonrelapse mortality in LA GVHD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
A role delineation study of hand surgery Steyers, C M; Chai, S H; Blair, W F ...
The Journal of hand surgery (American ed.),
09/1990, Volume:
15, Issue:
5
Journal Article
Peer reviewed
In 1986, The American Association for Hand Surgery and the American Society for Surgery of the Hand jointly sponsored a Role Delineation Study of Hand Surgery. The purpose of this study was to define ...the knowledge and skills necessary for competent hand surgery practice and to determine the responsibilities and activities of hand surgeons. Eight hundred thirty-eight hand surgeons returned a self-report questionnaire. This questionnaire was designed to collect information relative to the demographic characteristics of the respondents, the importance of 38 surgical procedures, and 60 categories of knowledge related to hand surgery, and to elicit respondents opinions regarding certification in hand surgery. This study is a first attempt to define the domain of hand surgery. The data collected in this study provide the basis for designing residency fellowship and continuing education programs and may also be used to study manpower needs, regional variations in practice patterns, and to identify the educational needs of the profession of hand surgery.
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