Hydrocephalus, characterized by cerebral ventriculomegaly, is the most common disorder requiring brain surgery in children. Recent studies have implicated SMARCC1, a component of the BRG1-associated ...factor (BAF) chromatin remodelling complex, as a candidate congenital hydrocephalus gene. However, SMARCC1 variants have not been systematically examined in a large patient cohort or conclusively linked with a human syndrome. Moreover, congenital hydrocephalus-associated SMARCC1 variants have not been functionally validated or mechanistically studied in vivo. Here, we aimed to assess the prevalence of SMARCC1 variants in an expanded patient cohort, describe associated clinical and radiographic phenotypes, and assess the impact of Smarcc1 depletion in a novel Xenopus tropicalis model of congenital hydrocephalus. To do this, we performed a genetic association study using whole-exome sequencing from a cohort consisting of 2697 total ventriculomegalic trios, including patients with neurosurgically-treated congenital hydrocephalus, that total 8091 exomes collected over 7 years (2016-23). A comparison control cohort consisted of 1798 exomes from unaffected siblings of patients with autism spectrum disorder and their unaffected parents were sourced from the Simons Simplex Collection. Enrichment and impact on protein structure were assessed in identified variants. Effects on the human fetal brain transcriptome were examined with RNA-sequencing and Smarcc1 knockdowns were generated in Xenopus and studied using optical coherence tomography imaging, in situ hybridization and immunofluorescence. SMARCC1 surpassed genome-wide significance thresholds, yielding six rare, protein-altering de novo variants localized to highly conserved residues in key functional domains. Patients exhibited hydrocephalus with aqueductal stenosis; corpus callosum abnormalities, developmental delay, and cardiac defects were also common. Xenopus knockdowns recapitulated both aqueductal stenosis and cardiac defects and were rescued by wild-type but not patient-specific variant SMARCC1. Hydrocephalic SMARCC1-variant human fetal brain and Smarcc1-variant Xenopus brain exhibited a similarly altered expression of key genes linked to midgestational neurogenesis, including the transcription factors NEUROD2 and MAB21L2. These results suggest de novo variants in SMARCC1 cause a novel human BAFopathy we term 'SMARCC1-associated developmental dysgenesis syndrome', characterized by variable presence of cerebral ventriculomegaly, aqueductal stenosis, developmental delay and a variety of structural brain or cardiac defects. These data underscore the importance of SMARCC1 and the BAF chromatin remodelling complex for human brain morphogenesis and provide evidence for a 'neural stem cell' paradigm of congenital hydrocephalus pathogenesis. These results highlight utility of trio-based whole-exome sequencing for identifying pathogenic variants in sporadic congenital structural brain disorders and suggest whole-exome sequencing may be a valuable adjunct in clinical management of congenital hydrocephalus patients.
Genomic instability is a hallmark of cancer, and has a central role in the initiation and development of breast cancer
. The success of poly-ADP ribose polymerase inhibitors in the treatment of ...breast cancers that are deficient in homologous recombination exemplifies the utility of synthetically lethal genetic interactions in the treatment of breast cancers that are driven by genomic instability
. Given that defects in homologous recombination are present in only a subset of breast cancers, there is a need to identify additional driver mechanisms for genomic instability and targeted strategies to exploit these defects in the treatment of cancer. Here we show that centrosome depletion induces synthetic lethality in cancer cells that contain the 17q23 amplicon, a recurrent copy number aberration that defines about 9% of all primary breast cancer tumours and is associated with high levels of genomic instability
. Specifically, inhibition of polo-like kinase 4 (PLK4) using small molecules leads to centrosome depletion, which triggers mitotic catastrophe in cells that exhibit amplicon-directed overexpression of TRIM37. To explain this effect, we identify TRIM37 as a negative regulator of centrosomal pericentriolar material. In 17q23-amplified cells that lack centrosomes, increased levels of TRIM37 block the formation of foci that comprise pericentriolar material-these foci are structures with a microtubule-nucleating capacity that are required for successful cell division in the absence of centrosomes. Finally, we find that the overexpression of TRIM37 causes genomic instability by delaying centrosome maturation and separation at mitotic entry, and thereby increases the frequency of mitotic errors. Collectively, these findings highlight TRIM37-dependent genomic instability as a putative driver event in 17q23-amplified breast cancer and provide a rationale for the use of centrosome-targeting therapeutic agents in treating these cancers.
Hypoxia is a common feature of locally advanced breast cancers that is associated with increased metastasis and poorer survival. Stabilisation of hypoxia-inducible factor-1α (HIF1α) in tumours causes ...transcriptional changes in numerous genes that function at distinct stages of the metastatic cascade. We demonstrate that expression of RIOK3 (RIght Open reading frame kinase 3) was increased during hypoxic exposure in an HIF1α-dependent manner. RIOK3 was localised to distinct cytoplasmic aggregates in normoxic cells and underwent redistribution to the leading edge of the cell in hypoxia with a corresponding change in the organisation of the actin cytoskeleton. Depletion of RIOK3 expression caused MDA-MB-231 to become elongated and this morphological change was due to a loss of protraction at the trailing edge of the cell. This phenotypic change resulted in reduced cell migration in two-dimensional cultures and inhibition of cell invasion through three-dimensional extracellular matrix. Proteomic analysis identified interactions of RIOK3 with actin and several actin-binding factors including tropomyosins (TPM3 and TPM4) and tropomodulin 3. Depletion of RIOK3 in cells resulted in fewer and less organised actin filaments. Analysis of these filaments showed reduced association of TPM3, particularly during hypoxia, suggesting that RIOK3 regulates actin filament specialisation. RIOK3 depletion reduced the dissemination of MDA-MB-231 cells in both a zebrafish model of systemic metastasis and a mouse model of pulmonary metastasis. These findings demonstrate that RIOK3 is necessary for maintaining actin cytoskeletal organisation required for migration and invasion, biological processes that are necessary for hypoxia-driven metastasis.
The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and ...societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
Gastric cancer represents the third leading cause of global cancer mortality and an area of unmet clinical need. Drugs that target the DNA damage response, including ATR inhibitors (ATRi), have been ...proposed as novel targeted agents in gastric cancer. Here, we sought to evaluate the efficacy of ATRi in preclinical models of gastric cancer and to understand how ATRi resistance might emerge as a means to identify predictors of ATRi response. A positive selection genome-wide CRISPR-Cas9 screen identified candidate regulators of ATRi resistance in gastric cancer. Loss-of-function mutations in either SMG8 or SMG9 caused ATRi resistance by an SMG1-mediated mechanism. Although ATRi still impaired ATR/CHK1 signaling in SMG8/9-defective cells, other characteristic responses to ATRi exposure were not seen, such as changes in ATM/CHK2, γH2AX, phospho-RPA, or 53BP1 status or changes in the proportions of cells in S- or G2-M-phases of the cell cycle. Transcription/replication conflicts (TRC) elicited by ATRi exposure are a likely cause of ATRi sensitivity, and SMG8/9-defective cells exhibited a reduced level of ATRi-induced TRCs, which could contribute to ATRi resistance. These observations suggest ATRi elicits antitumor efficacy in gastric cancer but that drug resistance could emerge via alterations in the SMG8/9/1 pathway.
These findings reveal how cancer cells acquire resistance to ATRi and identify pathways that could be targeted to enhance the overall effectiveness of these inhibitors.
A remote catheter navigation system compatible with magnetic resonance imaging (MRI) has been developed to facilitate MRI-guided catheterization procedures. The interventionalist's conventional ...motions (axial motion and rotation) on an input catheter - acting as the master - are measured by a pair of optical encoders, and a custom embedded system relays the motions to a pair of ultrasonic motors. The ultrasonic motors drive the patient catheter (slave) within the MRI scanner, replicating the motion of the input catheter. The performance of the remote catheter navigation system was evaluated in terms of accuracy and delay of motion replication outside and within the bore of the magnet. While inside the scanner bore, motion accuracy was characterized during the acquisition of frequently used imaging sequences, including real-time gradient echo. The effect of the catheter navigation system on image signal-to-noise ratio (SNR) was also evaluated. The results show that the master-slave system has a maximum time delay of 41 ± 21 ms in replicating motion; an absolute value error of 2 ± 2° was measured for radial catheter motion replication over 360° and 1.0 ± 0.8 mm in axial catheter motion replication over 100 mm of travel. The worst-case SNR drop was observed to be 2.5%.
Abstract Background Localized prostate cancer is clinically heterogeneous, despite clinical risk groups that represent relative prostate cancer-specific mortality. We previously developed a 100-locus ...DNA classifier capable of substratifying patients at risk of biochemical relapse within clinical risk groups. Objective The 100-locus genomic classifier was refined to 31 functional loci and tested with standard clinical variables for the ability to predict biochemical recurrence (BCR) and metastasis. Design, setting, and participants Four retrospective cohorts of radical prostatectomy specimens from patients with localized disease were pooled, and an additional 102-patient cohort used to measure the 31-locus genomic classifier with the NanoString platform. Outcome measurements and statistical analysis The genomic classifier scores were tested for their ability to predict BCR ( n = 563) and metastasis ( n = 154), and compared with clinical risk stratification schemes. Results and limitations The 31-locus genomic classifier performs similarly to the 100-locus classifier. It identifies patients with elevated BCR rates (hazard ratio = 2.73, p < 0.001) and patients that eventually develop metastasis (hazard ratio = 7.79, p < 0.001). Combining the genomic classifier with standard clinical variables outperforms clinical models. Finally, the 31-locus genomic classifier was implemented using a NanoString assay. The study is limited to retrospective cohorts. Conclusions The 100-locus and 31-locus genomic classifiers reliably identify a cohort of men with localized disease who have an elevated risk of failure. The NanoString assay will be useful for selecting patients for treatment deescalation or escalation in prospective clinical trials based on clinico-genomic scores from pretreatment biopsies. Patient summary It is challenging to determine whether tumors confined to the prostate are aggressive, leading to significant undertreatment and overtreatment. We validated a test based on prostate tumor DNA that improves estimations of relapse risk, and that can help guide treatment planning.
Spinal surgery is taught and practiced within 2 different surgical disciplines: neurological surgery and orthopedic surgery. We have provided a unified analysis of spine-focused faculty at U.S. ...residency programs.
A total of 278 Accreditation Council for Graduate Medical Education training programs were assessed to identify 923 full-time faculty members with a spinal surgery designation, defined by spine fellowship training or surgeon case volume >75% spine surgeries. Faculty were assessed with respect to parent discipline, years of fellowship training, academic rank, gender, and academic productivity (h-index).
The spine-teaching workforce contains 55% orthopedic surgeons and 45% neurosurgeons with wide gender asymmetry overall and at all faculty ranks. Of the female spine surgeons, those with neurosurgical training (64.44%) nearly doubled the number with orthopedic training (35.56%). Academic productivity increased with academic rank similarly for both genders and subspecialties. Orthopedic spine surgeons had a greater mean fellowship number compared with the neurological spine surgeons. Fellowship time of completion (intraresidency/infolded vs. postresidency) did not significantly affect the h-indexes. Addition of fellowship conferred academic productivity benefit for orthopedic surgeons only.
Neurological and orthopedic spine surgery showed similar patterns for the spread of faculty across academic ranks and trends in academic productivity. Marked gender disparity was seen in both neurosurgical and orthopedic surgery, with fewer female spine surgeons seen at every academic rank. Orthopedic spine surgeons had a greater mean fellowship number than did their neurosurgical counterparts, and a lack of fellowship correlated with lower academic productivity in orthopedic, but not neurological, spine surgery.
•The spine-teaching workforce contained 923 surgeons, 55% of whom were orthopedic surgeons.•Of the neurological spine surgeons and orthopedic spine surgeons 7.0% and 3.2% were women, respectively.•Academic productivity was not different between male and female spine surgeons.•Intra- versus postresidency fellowship timing did not affect academic productivity.•Orthopedic spine surgeons without a fellowship had a lower mean h-index.
Spinal surgery is taught and practiced within 2 different surgical disciplines, neurological surgery and orthopedic surgery. We have provided a unified analysis of academic productivity measured ...using the h-index attributable to spine-focused faculty at U.S. residency programs.
A total of 278 Accreditation Council for Graduate Medical Education training programs were assessed to identify 923 full-time faculty members with a spinal surgery designation, as defined by spine fellowship training or case volume >75% in spine surgery. The faculty were assessed with respect to academic rank, duration of practice in years, and academic productivity (h-index).
The comparison showed a significantly greater mean h-index for neurological spine surgeons. The mean h-index for both disciplines increased significantly as faculty rank increased. Within the academic ranks of assistant and associate professor, neurological spine surgeons had significantly greater mean h-indexes. Neurological spine surgeons had a significantly lower practice duration. At all ranks except for assistant professor, the mean practice duration was not significantly different statistically between the neurological spine and orthopedic spine surgeons. A positive correlation between the h-index and practice duration was found for both spine surgical disciplines. The proportional odds models for neurological and orthopedic spine surgeons were moderately successful at predicting faculty rank according to the h-index.
We present a unified view of academic productivity as measured by the h-index among neurosurgical and orthopedic surgery spine faculty, with some noticeable differences. These results can be used for benchmark purposes to assess the relative productivity of its faculty and could be of interest to those pursuing academic opportunities in spine surgery.
•Within spine surgery, neurosurgeons have a greater mean h-index.•For the rank of assistant and associate professor, neurosurgeons have a greater h-index.•The duration of practice was lower for neurosurgeons at the rank of assistant professor only.•The duration of practice and the h-index correlated positively for both specialties.•Faculty rank can be predicted for both specialties using the h-index.
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