Susceptibility to asthma depends on variation at an unknown number of genetic loci. To identify susceptibility genes on chromosome 7p, we adopted a hierarchical genotyping design, leading to the identification of a 133-kilobase risk-conferring segment containing two genes. One of these coded for an orphan G protein-coupled receptor named GPRA (G protein-coupled receptor for asthma susceptibility), which showed distinct distribution of protein isoforms between bronchial biopsies from healthy and asthmatic individuals. In three cohorts from Finland and Canada, single nucleotide polymorphism-tagged haplotypes associated with high serum immunoglobulin E or asthma. The murine ortholog of GPRA was up-regulated in a mouse model of ovalbumin-induced inflammation. Together, these data implicate GPRA in the pathogenesis of atopy and asthma.

A second distinct family of anion exchangers, SLC26, in addition to the classical SLC4 (or anion exchanger) family, has recently been delineated. Particular interest in this gene family is stimulated by the fact that the SLC26A2, SLC26A3, and SLC26A4 genes have been recognized as the disease genes mutated in diastrophic dysplasia, congenital chloride diarrhea, and Pendred syndrome, respectively. We report the expansion of the SLC26 gene family by characterizing three novel tissuespecific members, named SLC26A7, SLC26A8, and SLC26A9, on chromosomes 8, 6, and 1, respectively. The SLC26A7-A9 proteins are structurally very similar at the amino acid level to the previous family members and show tissue-specific expression in kidney, testis, and lung, respectively. More detailed characterization by immunohistochemistry and/or in situ hybridization localized SLC26A7 to distal segments of nephrons, SLC26A8 to developing spermatocytes, and SLC26A9 to the lumenal side of the bronchiolar and alveolar epithelium of lung. Expression of SLC26A7-A9 proteins in Xenopus oocytes demonstrated chloride, sulfate, and oxalate transport activity, suggesting that they encode functional anion exchangers. The functional characterization of the novel tissue-specific members may provide new insights to anion transport physiology in different parts of body.The systematic characterization of gene families using full genome sequences provides a rich source for expanding our physiological understanding of body functions. Recently, a second distinct family of anion exchangers, SLC26, has been delineated. The members of the SLC26 1 family are structurally well conserved across different species and can mediate the electroneutral exchange of Cl Ϫ for HCO 3 Ϫ across the plasma membrane of mammalian cells like members of the classical SLC4 (anion exchanger) family (1-3). Specific interest in the SLC26 gene family is stimulated by the fact that the first three human genes are associated with phenotypically distinct recessive diseases. The SLC26A2, SLC26A3, and SLC26A4 genes have been recognized as disease genes mutated in diastrophic dysplasia, congenital chloride diarrhea, and Pendred syndrome, respectively (4 -6). Thus, the three closely related but highly tissue-specific human anion transporters play central roles in the etiology of phenotypically very different recessive diseases.In human, six tissue-specific genes of the SLC26 family have been cloned so far, namely SLC26A1-A4 (previously known as SAT-1, DTDST, CLD or DRA, and PDS, respectively), SLC26A6, and TAT1. The SLC26A2-A4 members have been shown to transport, with different specificities, the chloride, iodide, bicarbonate, oxalate, and hydroxyl anions (7-12). SLC26A5 has been cloned from gerbil and rat and shown to act as a motor protein of cochlear outer hair cell; it is sensitive to intracellular anions but has not been found to act as a transporter (13,14). The SLC26A6 protein is expressed at highest levels in the kidney and the pancreas and suggested SLC26A6 as a candidate for a yet u...

Background: Programmed cell death protein 1 (PD-1) blocking monoclonal antibodies improve the overall survival of patients with advanced melanoma but the optimal duration of treatment has not been established. Patients and Methods: This academic real-world cohort study investigated the outcome of 185 advanced melanoma patients who electively discontinued anti-PD-1 therapy with pembrolizumab (N ¼ 167) or nivolumab (N ¼ 18) in the absence of disease progression (PD) or treatment limiting toxicity (TLT) at 14 medical centres across Europe and Australia. Results: Median time on treatment was 12 months (range 0.7-43). The best objective tumour response at the time of treatment discontinuation was complete response (CR) in 117 (63%) patients, partial response (PR) in 44 (24%) patients and stable disease (SD) in 16 (9%) patients; 8 (4%) patients had no evaluable disease (NE). After a median follow-up of 18 months (range 0.7-48) after treatment discontinuation, 78% of patients remained free of progression. Median time to progression was 12 months (range 2-23). PD was less frequent in patients with CR (14%) compared with patients with PR (32%) and SD (50%). Six out of 19 (32%) patients who were retreated with an anti-PD-1 at the time of PD obtained a new antitumour response. Conclusions: In this real-world cohort of advanced melanoma patients discontinuing anti-PD-1 therapy in the absence of TLT or PD, the duration of anti-PD-1 therapy was shorter when compared with clinical trials. In patients obtaining a CR, and being treated for >6 months, the risk of relapse after treatment discontinuation was low. Patients achieving a PR or SD as best tumour response were at higher risk for progression after discontinuing therapy, and defining optimal treatment duration in such patients deserves further study. Retreatment with an anti-PD-1 at the time of progression may lead to renewed antitumour activity in some patients.

Congenital chloride diarrhea (CLD) is an autosomal recessive disorder with around 250 cases reported so far. Life-long secretory diarrhea is caused by mutations in the solute carrier family 26 member 3 (SLC26A3) gene disrupting the epithelial Cl À /HCO 3 À transport in the ileum and colon. Although salt substitution allows favorable outcome, possible manifestations include renal impairment, intestinal inflammation, and male infertility. At least 55 mutations, of which 21 (38%) novel are reported here, cause CLD. Majority of the mutations are single nucleotide substitutions (n 5 30; 55%) with 18 missense, 7 nonsense, and 5 splice-site mutations. Additional mutations are minor deletions/insertions or their combinations (n 5 21; 38%), major deletions (n 5 3; 5%), and a major insertion (n 5 1; 2%). Distinct founder mutations appear in Finland, Poland, and Arab countries, whereas patients from other countries carry rare homozygous or compound heterozygous mutations. None of the studied SLC26A3 mutants shows significant Cl