UNG CANCER IS THE MOST COMmonly diagnosed cancer worldwide (1.35 million/year) and also the most frequent cause of cancer death (1.18 million/year). 1 Clinical staging of lung cancer is an integral part of patient care because it directs therapy and has prognostic value. Imaging with computed tomography (CT) is valuable for assessing the primary tumor (T-stage) while fluorodeoxyglucose positron emission tomography (PET) is valuable for detecting metastases. In cases where the primary tumor is resectable and in the ab-For editorial comment see p 2296.

Galloway-Mowat syndrome (GAMOS) is a severe autosomal-recessive disease characterized by the combination of early-onset steroid-resistant nephrotic syndrome (SRNS) and microcephaly with brain anomalies. To date, mutations of WDR73 are the only known monogenic cause of GAMOS and in most affected individuals the molecular diagnosis remains elusive. We here identify recessive mutations of OSGEP, TP53RK, TPRKB, or LAGE3, encoding the 4 subunits of the KEOPS complex in 33 individuals of 30 families with GAMOS. CRISPR/Cas9 knockout in zebrafish and mice recapitulates the human phenotype of microcephaly and results in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibits cell proliferation, which human mutations fail to rescue, and knockdown of either gene activates DNA damage response signaling and induces apoptosis. OSGEP and TP53RK molecularly interact and co-localize with the actin-regulating ARP2/3 complex. Furthermore, knockdown of OSGEP and TP53RK induces defects of the actin cytoskeleton and reduces migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identify 4 novel monogenic causes of GAMOS, describe the first link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.

We present 3 cases of large B-cell lymphoma (LBCL) with a granular cytoplasmic staining for anaplastic lymphoma kinase (ALK). All of the cases showed striking similarities in morphology and immunohistochemical profile characterized by a massive monomorphic proliferation of CD20 ؊ /CD138 ؉ plasmablast-like cells. In one of the cases, initially diagnosed as a null-type anaplastic large cell lymphoma (ALCL), the B-cell phenotype became evident only at recurrence. Fluorescent in situ hybridization (FISH) and molecular studies led to the detection of a CLTC-ALK rearrangement in all 3 cases, without any evidence of full-length ALK receptor expression. The associated t(2;17)(p23;q23) was demonstrated in the karyotype of 2 cases. Although a similar CLTC-ALK aberration was previously identified in ALK-positive T-/null cell ALCL and inflammatory myofibroblastic tumor, its association with ALK-positive LBCL seems to be specific and intriguing.

Autosomal-dominant tubulo-interstitial kidney disease (ADTKD) encompasses a group of disorders characterized by renal tubular and interstitial abnormalities, leading to slow progressive loss of kidney function requiring dialysis and kidney transplantation. Mutations in UMOD, MUC1, and REN are responsible for many, but not all, cases of ADTKD. We report on two families with ADTKD and congenital anemia accompanied by either intrauterine growth retardation or neutropenia. Ultrasound and kidney biopsy revealed small dysplastic kidneys with cysts and tubular atrophy with secondary glomerular sclerosis, respectively. Exclusion of known ADTKD genes coupled with linkage analysis, whole-exome sequencing, and targeted re-sequencing identified heterozygous missense variants in SEC61A1-c.553A>G (p.Thr185Ala) and c.200T>G (p.Val67Gly)-both affecting functionally important and conserved residues in SEC61. Both transiently expressed SEC6A1A variants are delocalized to the Golgi, a finding confirmed in a renal biopsy from an affected individual. Suppression or CRISPR-mediated deletions of sec61al2 in zebrafish embryos induced convolution defects of the pronephric tubules but not the pronephric ducts, consistent with the tubular atrophy observed in the affected individuals. Human mRNA encoding either of the two pathogenic alleles failed to rescue this phenotype as opposed to a complete rescue by human wild-type mRNA. Taken together, these findings provide a mechanism by which mutations in SEC61A1 lead to an autosomal-dominant syndromic form of progressive chronic kidney disease. We highlight protein translocation defects across the endoplasmic reticulum membrane, the principal role of the SEC61 complex, as a contributory pathogenic mechanism for ADTKD.

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BackgroundCervical cancer is the most frequent cancer of women in the Democratic Republic of Congo (DRC). Nevertheless, the level of women’s awareness about cervical cancer is unknown. Knowledge, attitude and practice (KAP) are important elements for designing and monitoring screening programs. The study purpose was to estimate KAP on cervical cancer and to identify associated factors.MethodsA cross-sectional study was conducted in Kinshasa, DRC, including 524 women aged 16–78 years (median age 28; interquartile range 22–35). The women were interviewed at home by trained field workers using a standardized questionnaire. The women’s score on knowledge, attitude and practice were dichotomized as sufficient or insufficient. We used binary and multiple logistic regression to assess associations between obtaining sufficient scores and a series of socio-demographic factors: age, residence, marital status, education, occupation, religion, and parity.ResultsThe women’s score on knowledge was not significantly correlated with their score on practice (Spearman’s rho = 0.08; P > 0.05). Obtaining a sufficient score on knowledge was positively associated with higher education (adjusted odds ratio (OR) 7.65; 95% confidence interval (95% CI) 3.31-17.66) and formal employment (adjusted OR 3.35; 95% CI 1.85-6.09); it was negatively associated with being single (adjusted OR 0.44; 95% CI 0.24-0.81) and living in the eastern, western and northern zone of Kinshasa compared to the city centre. The attitude score was associated with place of residence (adjusted OR for east Kinshasa: 0.49; 95% CI 0.27-0.86 and for south Kinshasa: 0.48; 95% CI 0.27-0.85) and with religion (adjusted OR 0.55; 95% CI 0.35-0.86 for women with a religion other than Catholicism or Protestantism compared to Catholics). Regarding practice, there were negative associations between a sufficient score on practice and being single (adjusted OR 0.24; 95% CI 0.13-0.41) and living in the eastern zone of the city (adjusted OR 0.39; 95% CI 0.22-0.70). Although 84% of women had heard about cervical cancer, only 9% had ever had a Papanicolaou (Pap) smear test.ConclusionsThis study shows a low level of knowledge, attitude and practice on cervical cancer among women in Kinshasa. Increasing women’s awareness would be a first step in the long chain of conditions to attain a lower incidence and mortality.

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This study was designed to examine the cellular distribution of the angiotensin II type-1 (AT1) and type-2 (AT2) receptors in the normal human and pathological human lung. Riboprobes were prepared against specific portions of each receptor DNA and labelled with FITC for detection using an anti-FITC antibody in combination with the alkaline phosphatase-anti-alkaline phosphatase technique and new Fuchsin. These were used to detect the presence of receptor mRNA in the lung. Specific antibodies were used to detect receptor protein in cells by immunocytochemistry. Image analysis was used in order to semi-quantify receptor density. AT1 receptor mRNA and protein were localised on vascular smooth muscle cells, macrophages and in the stroma underlying the airways epithelium probably relating to underlying fibroblasts. The AT1 receptor protein was not expressed in the epithelium although there was a low level of mRNA. In contrast, AT2 receptor RNA and protein was observed in the epithelium, with strong staining on the bronchial epithelial cell brush border and also on many of the underlying mucous glands. The AT2 receptor was also present on some endothelial cells. These findings were supported by the presence of mRNA in each case. In patients with chronic obstructive pulmonary disease, there was a five- to sixfold increase in the ratio of AT1 to AT2 receptors in the regions of marked fibrosis surrounding the bronchioles. This correlated well with the reduced lung function as expressed by the forced expiratory volume.