Crystal structure of the incretin-bound extracellular domain of a G protein-coupled receptor

Incretins, endogenous polypeptide hormones released in response to food intake, potentiate insulin secretion from pancreatic beta cells after oral glucose ingestion (the incretin effect). This response is signaled by the two peptide hormones glucose-dependent insulinotropic polypeptide (GIP) (also known as gastric inhibitory polypeptide) and glucagon-like peptide 1 through binding and activation of their cognate class 2 G protein-coupled receptors (GPCRs). Because the incretin effect is lost or significantly reduced in patients with type 2 diabetes mellitus, glucagon-like peptide 1 and GIP have attracted considerable attention for their potential in antidiabetic therapy. A paucity of structural information precludes a detailed understanding of the processes of hormone binding and receptor activation, hampering efforts to develop novel pharmaceuticals. Here we report the crystal structure of the complex of human GIP receptor extracellular domain (ECD) with its agonist, the incretin GIP(1-42). The hormone binds in an alpha-helical conformation in a surface groove of the ECD largely through hydrophobic interactions. The N-terminal ligand residues would remain free to interact with other parts of the receptor. Thermodynamic data suggest that binding is concomitant with structural organization of the hormone, resulting in a complex mode of receptor-ligand recognition. The presentation of a well structured, alpha-helical ligand by the ECD is expected to be conserved among other hormone receptors of this class.     

The clinical manifestation of a defective response to DNA double-strand breaks as exemplified by Nijmegen breakage syndrome

The autosomal recessive genetic disorder Nijmegen breakage syndrome (NBS) was first described in 1981 in patients living in Nijmegen, Holland. NBS patients display a characteristic facial appearance, microcephaly and a range of symptoms including immunodeficiency, increased cancer risk and growth retardation. In addition, NBS patient cells were found to have elevated levels of chromosomal damage and to be sensitive to ionizing irradiation (IR). This radiosensitivity had fatal consequences in some undiagnosed patients. The most dangerous DNA lesion caused by IR is considered to be the double-strand break (DSB) and indeed, NBS patient cells are sensitive to all mutagens that produce DSBs directly or indirectly. We discuss here our current understanding of how a deficiency in DSB repair manifests as the particular symptom complex of NBS.     

Epidemiology,management, and burden of cytomegalovirus in solid organ transplant recipients in selected countries outside of Europe and North America: A systematic review

Background

Cytomegalovirus (CMV) is a frequent infectious complication following solid organ transplantation (SOT). Considering significant differences in healthcare systems, a systematic review was conducted to describe the epidemiology, management, and burden of CMV post-SOT in selected countries outside of Europe and North America.

Methods

MEDLINE, Embase, and Cochrane databases were searched for observational studies in SOT recipients across 15 countries in the regions of Asia, Pacific, and Latin America (search period: January 1, 2011 to September 17, 2021). Outcomes included incidence of CMV infection/disease, recurrence, risk factors, CMV-related mortality, treatment patterns and guidelines, refractory and/or resistant CMV, patient-reported outcomes, and economic burden.

Results

Of 2708 studies identified, 49 were eligible (n = 43/49; 87.8% in adults; n = 34/49, 69.4% in kidney recipients). Across studies, selection of CMV preventive strategy was based on CMV serostatus. Overall, rates of CMV infection (within 1 year) and CMV disease post-SOT were respectively, 10.3%–63.2% (9 studies) and 0%–19.0% (17 studies). Recurrence occurred in 35.4%–41.0% cases (3 studies) and up to 5.3% recipients died of CMV-associated causes (11 studies). Conventional treatments for CMV infection/disease included ganciclovir (GCV) or valganciclovir. Up to 4.4% patients were resistant to treatment (3 studies); no studies reported on refractory CMV. Treatment-related adverse events with GCV included neutropenia (2%–29%), anemia (13%–48%), leukopenia (11%–37%), and thrombocytopenia (13%–24%). Data on economic burden were scarce.

     

Epidemiology,treatment patterns,and disease burden of cytomegalovirus in hematopoietic cell transplant recipients in selected countries outside of Europe and North America: A systematic review

Background

Cytomegalovirus (CMV) disease impacts morbidity and mortality in hematopoietic cell transplant (HCT) recipients. This systematic review summarized data on the epidemiology, management, and burden of CMV post-HCT outside of Europe and North America.

Methods

The MEDLINE, Embase, and Cochrane databases were searched for observational studies and treatment guidelines in HCT recipients across 15 selected countries from Asia-Pacific, Latin America, and Middle East (search period: 1 January 2011–17 September 2021). Outcomes included incidence of CMV infection/disease, recurrence, risk factors, CMV-related mortality, treatments, refractory, resistant CMV, and burden.

Results

Of 2708 references identified, 68 were eligible (67 studies and one guideline; 45/67 studies specific to adult allogeneic HCT recipients). The rates of CMV infection and disease within 1 year of allogeneic HCT were 24.9%–61.2% (23 studies) and 2.9%–15.7% (10 studies), respectively. Recurrence occurred in 19.8%–37.9% of cases (11 studies). Up to 10% of HCT recipients died of CMV-related causes. In all countries, first-line treatment for CMV infection/disease involved intravenous ganciclovir or valganciclovir. Conventional treatments were associated with serious adverse events such as myelosuppression (10.0%) or neutropenia only (30.0%, 39.8%) and nephrotoxicity (11.0%) (three studies), frequently leading to treatment discontinuation (up to 13.6%). Refractory CMV was reported in 2.9%, 13.0%, and 28.9% of treated patients (three studies) with resistant CMV diagnosed in 0%–10% of recipients (five studies). Patient-reported outcomes and economic data were scarce.

Conclusion

The incidence of CMV infection and disease post-HCT is high outside of North America and Europe. CMV resistance and toxicity highlight a major unmet need with current conventional treatments.