Lung morphogenesis relies on a number of important processes, including proximal-distal patterning, cell proliferation, migration and differentiation, as well as epithelial-mesenchymal interactions. ...In mouse lung development, SOX2
cells are localized in the proximal epithelium, whereas SOX9
cells are present in the distal epithelium. We show that, in human lung, expression of these transcription factors differs, in that during the pseudoglandular stage distal epithelial progenitors at the tips coexpress SOX2 and SOX9. This double-positive population was no longer present by the canalicular stages of development. As in mouse, the human proximal epithelial progenitors express solely SOX2 and are surrounded by smooth muscle cells (SMCs) both in the proximal airways and at the epithelial clefts. Upon Ras-related C3 botulinum toxin substrate 1 inhibition, we noted decreased branching, as well as increased SMC differentiation, attenuated peristalsis, and a reduction in the distal double-positive SOX2/SOX9 progenitor cell population. Thus, the presence of SOX2/SOX9 double-positive progenitor cells in the distal epithelium during the pseudoglandular stage of human lung development appears to be critical to proximal-distal patterning and lung branching. Moreover, SMCs promote a SOX2 proximal phenotype and seem to suppress the SOX9
population.
Current kidney organoids model development and diseases of the nephron but not the contiguous epithelial network of the kidney's collecting duct (CD) system. Here, we report the generation of an ...expandable, 3D branching ureteric bud (UB) organoid culture model that can be derived from primary UB progenitors from mouse and human fetal kidneys, or generated de novo from human pluripotent stem cells. In chemically-defined culture conditions, UB organoids generate CD organoids, with differentiated principal and intercalated cells adopting spatial assemblies reflective of the adult kidney's collecting system. Aggregating 3D-cultured nephron progenitor cells with UB organoids in vitro results in a reiterative process of branching morphogenesis and nephron induction, similar to kidney development. Applying an efficient gene editing strategy to remove RET activity, we demonstrate genetically modified UB organoids can model congenital anomalies of kidney and urinary tract. Taken together, these platforms will facilitate an enhanced understanding of development, regeneration and diseases of the mammalian collecting duct system.
Minimally invasive radical hysterectomy (MIS-RH) for early-stage cervical cancer is a relatively new surgical procedure with increased utilization in the mid-/late-2000s. This study examined the ...association between hospital surgical volume for MIS-RH and perioperative outcomes for early-stage cervical cancer in the period of early adoption.
This population-based retrospective study queried the National Inpatient Sample from 2007 to 2011. Cervical cancer cases treated with MIS-RH were examined (n = 2202 from 163 hospitals). Annualized hospital surgical volume was defined as the average number of procedures performed per year in which at least one case was performed. Characteristics and outcomes related to MIS-RH use were assessed. The comparator cohort included RH by laparotomy (Open-RH; n = 11,187 from 405 hospitals).
Among MIS-RH-offering centers, 42.3% had average 1 case/year and surgical volume of >4 cases/year represented the top decile. When stratified by MIS-RH types, on average 31.3 centers performed robotic-assisted approach per year versus 11.5 centers for the traditional approach. Small bed capacity centers were most likely to perform robotic-assisted RH (adjusted-odds ratio 4.07, P < 0.001). In the traditional MIS-RH group, higher hospital surgical volume was associated with lower surgical morbidity (P = 0.025) whereas in the robotic-assisted approach higher hospital surgical volume was associated with higher surgical morbidity (P < 0.001). In the Open-RH cohort, higher hospital surgical volume was significantly associated with decreased surgical morbidity and mortality (both, P < 0.001).
In the mid-/late-2000s, MIS-RH surgical volume was modest in the United States. Small bed capacity centers adopted robotic-assisted MIS-RH more frequently, and there was a statistically significant association of increased perioperative complications among higher volume centers. In contrast, higher surgical volume was associated with improved perioperative outcomes with the traditional MIS-RH and open-RH approaches.
•Volume-outcome relationship was examined for minimally-invasive radical hysterectomy (MIS-RH) from 2007 to 2011.•Small bedsize centers exhibited the largest effect size for robotic MIS-RH use.•Higher surgical volume was associated with lower perioperative complication in traditional MIS-RH and open-RH.•This inverse association for volume-outcome relationship was not observed in robotic MIS-RH during the study period.
To examine the association between malignant peritoneal cytology and survival in women with early-stage endometrioid endometrial cancer.
This is a retrospective cohort study using the Surveillance, ...Epidemiology, and End Results Program from 2010 to 2016. Women with stage I endometrioid endometrial cancer who had peritoneal cytology testing at hysterectomy were examined (N = 24,800). Characteristics and survival related to malignant peritoneal cytology were assessed. The propensity score inverse probability of treatment weighting was used to balance the measured covariates.
Malignant peritoneal cytology was reported in 1081 (4.4%) women. In multivariable analysis, stage IB disease and moderately/poorly differentiated tumours were associated with an increased likelihood of malignant peritoneal cytology (both P < 0.05). In a weighted model, malignant peritoneal cytology was associated with decreased cause-specific survival (5-year rates, 92.1% versus 96.8%, hazard ratio HR 1.98, 95% confidence interval CI 1.56–2.52) and overall survival (89.4% versus 93.1%, HR 1.41, 95% CI 1.16–1.72). In sensitivity analyses, malignant peritoneal cytology was associated with decreased overall survival in the high–intermediate-risk group (5-year rates, 77.8% versus 83.6%, HR 1.57, 95% CI 1.20–2.06) and decreased cause-specific survival in the low-risk group (95.4% versus 98.0%, HR 1.64, 95% CI 1.01–2.68). In the high–intermediate-risk group with malignant peritoneal cytology, postoperative chemotherapy was associated with improved overall survival compared to whole pelvic radiotherapy (5-year rates, 82.7% versus 64.6%, HR 0.36, 95% CI 0.14–0.96). This association was not observed in negative cytology cases (81.5% versus 79.7%, HR 0.78, 95% CI 0.53–1.14).
Malignant peritoneal cytology may be associated with decreased survival in stage I endometrioid endometrial cancer.
•Malignant peritoneal cytology was examined in stage I endometrioid endometrial cancer.•The US largest population-based tumour registry was queried (N = 24,800).•Malignant peritoneal cytology was seen in 4.4% of the patients.•Malignant peritoneal cytology was associated with decreased survival outcomes.•Systematic review and meta-analysis demonstrated the same association.
Most retinoblastomas initiate in response to the inactivation of the RB1 gene and loss of functional RB protein. The tumors may form with few additional genomic changes and develop after a ...premalignant retinoma phase. Despite this seemingly straightforward etiology, mouse models have not recapitulated the genetic, cellular, and stage-specific features of human retinoblastoma genesis. For example, whereas human retinoblastomas appear to derive from cone photoreceptor precursors, current mouse models develop tumors that derive from other retinal cell types. To investigate the basis of the human cone-specific oncogenesis, we compared developmental stage-specific cone precursor responses to RB loss in human and murine retina cultures and in cone-specific Rb1-knockout mice. We report that RB-depleted maturing (ARR3⁺) but not immature (ARR3⁻) human cone precursors enter the cell cycle, proliferate, and form retinoblastoma-like lesions with Flexner–Wintersteiner rosettes, then form low or nonproliferative premalignant retinoma-like lesions with fleurettes and p16INK4A and p130 expression, and finally form highly proliferative retinoblastoma-like masses. In contrast, inmurine retina, only RB-depleted immature (Arr3⁻) cone precursors entered the cell cycle, and they failed to progress from S to M phase. Moreover, whereas intrinsically highly expressed MDM2 and MYCN contribute to RB-depleted maturing (ARR3⁺) human cone precursor proliferation, ectopic MDM2 and Mycn promoted only immature (Arr3⁻) murine cone precursor cell-cycle entry. These findings demonstrate that developmental stage-specific as well as species- and cell type-specific features sensitize to RB1 inactivation and reveal the human cone precursors’ capacity to model retinoblastoma initiation, proliferation, premalignant arrest, and tumor growth.
Cardiac lymphatic vessels play important roles in fluid homeostasis, inflammation, disease, and regeneration of the heart. The developing cardiac lymphatics in human fetal hearts are closely ...associated with coronary arteries, similar to those in zebrafish hearts. We identify a population of cardiac lymphatic endothelial cells (LECs) that reside in the epicardium. Single-nuclei multiomic analysis of the human fetal heart reveals the plasticity and heterogeneity of the cardiac endothelium. Furthermore, we find that VEGFC is highly expressed in arterial endothelial cells and epicardium-derived cells, providing a molecular basis for the arterial association of cardiac lymphatic development. Using a cell-type-specific integrative analysis, we identify a population of cardiac lymphatic endothelial cells marked by the PROX1 and the lymphangiocrine RELN and enriched in binding motifs of erythroblast transformation specific (ETS) variant (ETV) transcription factors. We report the in vivo molecular characterization of human cardiac lymphatics and provide a valuable resource to understand fetal heart development.
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•Single-nuclei multiomic analyses of human fetal heart reveal cardiac LECs in epicardium•Cardiac lymphatic vessels are mainly associated with coronary arteries•Human fetal cardiac LECs express PROX1 and RELN•ETV2 binding motif is enriched in human fetal cardiac LECs
Travisano et al. integrate analyses of transcriptomics and the chromatin landscape of cardiac lymphatics of human fetal hearts. Cardiac lymphatic endothelial cells (LECs) are in the epicardium and associate preferentially with coronary arteries. These human fetal cardiac LECs show high PROX1 and RELN expression and have enriched ETV2 binding motifs.
To describe how population-based statistics for rare epithelial ovarian cancers are evolving.
This is a retrospective observational study examining the Surveillance, Epidemiology, and End Results ...Program from 1988 to 2016. Overall survival (OS) of clear cell (OCCC), mucinous (MOC), and low-grade serous (LGSOC) ovarian cancers were compared to high-grade serous ovarian cancer (HGSOC) by fitting a propensity score matching.
Among 113,365 ovarian malignancies, 5780 OCCCs (5.1%), 7561 MOCs (6.7%), and 2021 LGSOCs (1.8%) were compared to 38,199 HGSOCs. OCCCs and MOCs were more likely to be diagnosed with stage I disease compared to HGSOC (57.0–59.5% versus 8.6%, P<0.001). For early-stage disease, OCCC (hazard ratio HR 0.91, 95% confidence interval CI 0.82–1.01) and MOC (HR 0.94, 95%CI 0.85–1.04) had similar OS to HGSOC whereas LGSOC had superior OS (HR 0.93, 95%CI 0.89–0.97) versus HGSOC. Conversely, for advanced-stage disease, OCCC (HR 1.42, 95%CI 1.32–1.53) and MOC (HR 1.11, 95%CI 1.09–1.13) had poorer OS whereas LGSOC (HR 0.86, 95%CI 0.84–0.89) had superior OS compared to HGSOC. OCCC (HR range, 1.92–2.45) and MOC (HR range, 1.73–2.22) had particularly poorer OS in the first three years following diagnosis compared to HGSOC. Population-level statistics for advanced-stage disease showed that 5-year OS rates have increased in HGSOC (16.9% to 36.8%, P<0.001) and LGSOC (50.8% to 66.4%, P=0.010); but remain unchanged for OCCC (21.0% to 28.2%, P=0.174) and MOC (21.4% to 16.5%, P=0.102).
OCCC, MOC, and LGSOC comprise 2–7% of ovarian malignancies, have distinct characteristics and survival compared to HGSOC. While these rare tumors have a favorable to comparable prognosis in early-stage disease, disproportionally poor survival in advanced-stage OCCC and MOC highlights the need for further research into novel treatment strategies.
•Populational characteristics and outcomes of rare ovarian tumor were examined•OCCC, MOC, and LGSOC have distinct clinico-pathological characteristics compared to HGSOC•OCCC versus HGSOC: comparable survival in early disease while dismal survival in advanced disease•MOC versus HGSOC: comparable survival in early disease while dismal survival in advanced disease•LGSOC versus HGSOC: superior survival in both early and advanced disease
To examine the association between hospital surgical volume and perioperative outcomes for fertility-sparing trachelectomy performed for cervical cancer.
This is a population-based retrospective ...observational study utilizing the Nationwide Inpatient Sample from 2001 to 2011. Women aged ≤45 years with cervical cancer who underwent trachelectomy were included. Annualized hospital surgical volume was defined as the average number of trachelectomies a hospital performed per year in which at least one case was performed. Perioperative outcomes were assessed based on hospital surgical volume in a weighted model, specifically comparing the top-decile centers to the lower volume centers.
There were a total of 815 trachelectomies performed at 89 centers, and 76.4% of the trachelectomy-performing centers had a minimum surgical volume of one trachelectomy per year. The top-decile group had a higher rate of lymphadenectomy performance compared to the lower volume group (96.4% versus 82.4%, odds ratio OR 5.65, 95% confidence interval CI 2.81–11.4, P < 0.001). There was a significant inverse linear association between annualized surgical volume and the number of perioperative complications (P = 0.020). The top-decile group also had a lower rate of perioperative complications (9.7% versus 21.0%, P < 0.001) and prolonged hospital stay ≥7 days (2.0% versus 6.5%, P = 0.006) compared to the lower volume group. In a multivariable analysis, the top-decile group had a 65% relative decrease in perioperative complication risk compared to the lower volume group (adjusted-OR 0.35, 95%CI 0.20–0.59, P < 0.001).
Fertility-sparing trachelectomy for young women with cervical cancer is a rare surgical procedure; <90 centers performed this procedure from 2001 to 2011 and most hospitals perform a small number of cases annually. Higher hospital surgical volume for trachelectomy may be associated with reduced perioperative morbidity.
•A national study was conducted to examine volume-outcome relationship of fertility-sparing trachelectomy for cervical cancer.•Between 2001 and 2011, fewer than 90 centers performed fertility-sparing trachelectomy.•The majority of trachelectomy-performing centers had minimum surgical volume of one case a year.•Higher hospital surgical volume for trachelectomy may be associated with reduced short-term perioperative morbidity.
Lung maturation is not limited to proper structural development but also includes differentiation and functionality of various highly specialized alveolar cell types. Alveolar type 1 (AT1s) cells ...occupy nearly 95% of the alveolar surface and are critical for establishing efficient gas exchange in the mature lung. AT1 cells arise from progenitors specified during the embryonic stage as well as alveolar epithelial progenitors expressing surfactant protein C (Sftpcpos cells) during postnatal and adult stages. Previously, we found that Wnt5a, a non-canonical Wnt ligand, is required for differentiation of AT1 cells during the saccular phase of lung development. To further investigate the role of Wnt5a in AT1 cell differentiation, we generated and characterized a conditional Wnt5a gain-of-function mouse model. Neonatal Wnt5a gain-of-function disrupted alveologenesis through inhibition of cell proliferation. In this setting Wnt5a downregulated β-catenin-dependent canonical Wnt signaling, repressed AT2 (anti-AT2) and promoted AT1 (pro-AT1) lineage-specific gene expression. In addition, we identified 2 subpopulations of Sftpchigh and Sftpclow alveolar epithelial cells. In Sftpclow cells, Wnt5a exhibits pro-AT1 and anti-AT2 effects, concurrent with inhibition of canonical Wnt signaling. Interestingly, in the Sftpchigh subpopulation, although increasing AT1 lineage-specific gene expression, Wnt5a gain-of-function did not change AT2 gene expression, nor inhibit canonical Wnt signaling. Using primary epithelial cells isolated from human fetal lungs, we demonstrate that this property of Wnt5a is evolutionarily conserved. Wnt5a therefore serves as a selective regulator that ensures proper AT1/AT2 balance in the developing lung.
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