Harnessing cellular therapeutics for type 1 diabetes mellitus: progress, challenges, and the road ahead.

Type 1 diabetes mellitus (T1DM) is a growing global health concern that affects approximately 8.5 million individuals worldwide. T1DM is characterized by an autoimmune destruction of pancreatic β cells, leading to a disruption in glucose homeostasis.

A therapeutic convection-enhanced macroencapsulation device for enhancing β cell viability and insulin secretion.

Islet transplantation for type 1 diabetes treatment has been limited by the need for lifelong immunosuppression regimens. This challenge has prompted the development of macroencapsulation devices (MEDs) to immunoprotect the transplanted islets. While promising, conventional MEDs are faced with insufficient transport of oxygen, glucose, and insulin because of the reliance on passive diffusion.

3D Bioprinting and Translation of Beta Cell Replacement Therapies for Type 1 Diabetes.

Type 1 diabetes (T1D) is an autoimmune disorder in which the body's own immune system selectively attacks beta cells within pancreatic islets resulting in insufficient insulin production and loss of the ability to regulate blood glucose (BG) levels. Currently, the standard of care consists of BG level monitoring and insulin administration, which are essential to avoid the consequences of dysglycemia and long-term complications. Although recent advances in continuous glucose monitoring and automated insulin delivery systems have resulted in improved clinical outcomes for users, nearly 80% of people with T1D fail to achieve their target hemoglobin A1c (HbA1c) levels defined by the American Diabetes Association.

Transplantation of PEGylated islets enhances therapeutic efficacy in a diabetic nonhuman primate model.

Islet cell transplantation can lead to insulin independence, reduced hypoglycemia, and amelioration of diabetes complications in patients with type 1 diabetes. The systemic delivery of anti-inflammatory agents, while considered crucial to limit the early loss of islets associated with intrahepatic infusion, increases the burden of immunosuppression. In an effort to decrease the pharmaceutical load to the patient, we modified the pancreatic islet surface with long-chain poly(ethylene glycol) (PEG) to mitigate detrimental host-implant interactions.

The impact of cell surface PEGylation and short-course immunotherapy on islet graft survival in an allogeneic murine model.

Unlabelled: Islet transplantation is a promising therapy for Type 1 diabetes mellitus; however, host inflammatory and immune responses lead to islet dysfunction and destruction, despite potent systemic immunosuppression. Grafting of poly(ethylene glycol) (PEG) to the periphery of cells or tissues can mitigate inflammation and immune recognition via generation of a steric barrier. Herein, we sought to evaluate the complementary impact of islet PEGylation with a short-course immunotherapy on the survival of fully-MHC mismatched islet allografts (DBA/2 islets into diabetic C57BL/6J recipients).

Device design and materials optimization of conformal coating for islets of Langerhans.

Encapsulation of islets of Langerhans may represent a way to transplant islets in the absence of immunosuppression. Traditional methods for encapsulation lead to diffusional limitations imposed by the size of the capsules (600-1,000 μm in diameter), which results in core hypoxia and delayed insulin secretion in response to glucose. Moreover, the large volume of encapsulated cells does not allow implantation in sites that might be more favorable to islet cell engraftment.

Long-term survival of allograft murine islets coated via covalently stabilized polymers.

Clinical islet transplantation (CIT) has emerged as a promising treatment option for type 1 diabetes mellitus (T1DM); however, the antirejection drug regimen necessary to mitigate allograft islet rejection is undesirable. The use of polymeric coatings to immunocamouflage the transplant from host immune attack has great potential. Alginate and poly(ethylene glycol) (PEG)-based polymers, functionalized with azide and phosphine, respectively, which form spontaneous and chemoselective crosslinks via the bioorthogonal Staudinger ligation scheme, were recently developed.

Influence of in vitro and in vivo oxygen modulation on β cell differentiation from human embryonic stem cells.

The possibility of using human embryonic stem (hES) cell-derived β cells as an alternative to cadaveric islets for the treatment of type 1 diabetes is now widely acknowledged. However, current differentiation methods consistently fail to generate meaningful numbers of mature, functional β cells. In order to address this issue, we set out to explore the role of oxygen modulation in the maturation of pancreatic progenitor (PP) cells differentiated from hES cells.

TAT-mediated transduction of MafA protein in utero results in enhanced pancreatic insulin expression and changes in islet morphology.

Alongside Pdx1 and Beta2/NeuroD, the transcription factor MafA has been shown to be instrumental in the maintenance of the beta cell phenotype. Indeed, a combination of MafA, Pdx1 and Ngn3 (an upstream regulator of Beta2/NeuroD) was recently reported to lead to the effective reprogramming of acinar cells into insulin-producing beta cells. These experiments set the stage for the development of new strategies to address the impairment of glycemic control in diabetic patients.

Enhancing clinical islet transplantation through tissue engineering strategies.

Clinical islet transplantation (CIT), the infusion of allogeneic islets within the liver, has the potential to provide precise and sustainable control of blood glucose levels for the treatment of type 1 diabetes. The success and long-term outcomes of CIT, however, are limited by obstacles such as a nonoptimal transplantation site and severe inflammatory and immunological responses to the transplant. Tissue engineering strategies are poised to combat these challenges.

Enhanced oxygenation promotes beta-cell differentiation in vitro.

Despite progress in our knowledge about pancreatic islet specification, most attempts at differentiating stem/progenitor cells into functional, transplantable beta cells have met only with moderate success thus far. A major challenge is the intrinsic simplicity of in vitro culture systems, which cannot approximate the physiological complexity of in vivo microenvironments. Oxygenation is a critical limitation of standard culture methods, and one of special relevance for the development of beta cells, known for their high O(2) requirements.

[The effect of controlled physical activity on the body composition of postmenopausal sedentary women].

Objective: To evaluate the effect of a controlled physical activity program on the weight and body composition of healthy sedentary postmenopausal women.

Methods: From a group of 138 postmenopausal women volunteers, 18 of them were selected, using a survey that measured the frequency and intensity of their physical activity. These 18 women were classified as "sedentary," having an average daily energy expenditure (in terms of mL of oxygen per kg per minute) that was below 60% of the maximum oxygen consumption for their age.

Pure mucinous carcinoma of the breast: is axillary staging necessary?

Background: Mucinous carcinoma of the breast (MCB) may be associated with a low risk of axillary metastases.

Methods: To evaluate the incidence of axillary nodal metastasis in MCB, a review of all cases from January 1990 to July 2000 was performed. Pure MCB was defined as all tumor cells being completely surrounded by mucin.