Repressor element 1 silencing transcription factor (REST) controls radial migration and temporal neuronal specification during neocortical development.

Neurogenesis requires mechanisms that coordinate early cell-fate decisions, migration, and terminal differentiation. Here, we show that the transcriptional repressor, repressor element 1 silencing transcription factor (REST), regulates radial migration and the timing of neural progenitor differentiation during neocortical development, and that the regulation is contingent upon differential REST levels. Specifically, a sustained presence of REST blocks migration and greatly delays--but does not prevent--neuronal differentiation, resulting in a subcortical band heterotopia-like phenotype, reminiscent of loss of doublecortin. We further show that doublecortin is a direct gene target of REST, and that its overexpression rescues, at least in part, the aberrant phenotype caused by persistent presence of REST. Our studies support the view that the targeted down-regulation of REST to low levels in neural progenitors, and its subsequent disappearance during neurogenesis, is critical for timing the spatiotemporal transition of neural progenitor cells to neurons.

Successful Treatment of Vertebral Osteosarcoma in a Cat Using Marginal Surgical Excision and Chemotherapy.

A three-year-old male neutered Norwegian Forest cat was referred for bilateral ambulatory paraparesis and spinal pain. On magnetic resonance imaging (MRI), a mass involving the right epaxial muscles with vertebral canal invasion and causing marked extradural spinal cord compression was identified. At surgery, the mass was debulked and a right hemilaminectomy was performed. Histopathology was diagnostic of fibroblastic osteosarcoma. Residual osteolytic lesions of the osteosarcoma were present at the level of the spinous process of the second lumbar vertebra. Four cycles of adjuvant doxorubicin chemotherapy were administered followed by oral toceranib phosphate. Neurological signs improved gradually over weeks to months and the lesion in the spinous process was no longer visible on radiographs. At one year from diagnosis, an MRI of the T3-L3 (3rd thoracic vertebra to the 3rd lumbar vertebra) spinal region and a whole-body computer tomography (CT) scan found no evidence of the osteosarcoma in the spine or of any metastasis. All medications were stopped and, at the time of writing 16 months later, the patient is neurologically normal with no signs of cancer recurrence. This is the first case report documenting the complete resolution of vertebral osteosarcoma lesions after treatment with doxorubicin followed by toceranib phosphate. The treatment also prevented tumor recurrence and was associated with an exceptionally long-term survival time.

Robot-Assisted Simple Prostatectomy: Illustration of a Simplified Extraperitoneal Transcapsular Technique.

Introduction and Objectives: Robot-assisted simple prostatectomy (RASP) performed with the extraperitoneal (EP) technique (RASP-EP) minimizes the risk of bowel injury, particularly when bowel adhesions may be expected to be prominent, by negating the need to be in the transperitoneal space. However, there is a perception of its technical difficulty owing to the limited space that can be expanded within the space of Retzius. We aimed to describe, in the accompanying video, the step-by-step approach for a technically proficient procedure. Methods: From January 2010 to July 2018, 33 consecutive patients who had undergone RASP-EP were identified from our institutional database. Procedures were performed as described stepwise in the accompanying video. In RASP-EP, a 3 cm paraumbilical incision is made, anterior rectus sheath incised, muscle pushed laterally, and the EP space is entered. The EP space is expanded in the retropubic area using a balloon dilator and a blunt ended trocar, enabling the placement of further three ports for robot docking. A transverse capsulotomy, 2 cm from the bladder neck, is performed a la Millin's. Prostate adenoma is resected circumferentially. Electrocautery hemostasis is performed. Posterior bladder neck and urethra are sutured onto the prostatic fossa with 2-0 Vicryl. A 22F three-way catheter is placed. Anterior capsulotomy is closed in two layers with 2-0 and 0-0 Vicryl sutures. A drain is left in the retropubic space. Patient is discharged within 1-2 days with the catheter in situ, which is then removed 10 days later. Results: Of the 33 patients, median values were age (68), American Society of Anesthesiology (3), Charlson Comorbidity Index (3), and body mass index (28.5 kg/m2). Eight (24.2%) patients had prior abdominal surgeries. Twenty-five (75.8%) patients were catheter dependent. Adjunctive procedures were cystolithotomy (5), umbilical hernia repair (2), and ureteroscopy (1). Median values were operative time (178 minutes), estimated blood loss (200 mL), hemoglobin change (2.8 g/dL), and hematocrit change (9%); only one patient (3.0%) required 1 U transfusion. Median length of stay was 2 days. Clavien-Dindo complications were 0 (21), I (7), II (3), IIIa (1), IIIb (1), IV, and V (0). Median resected prostate weight was 122 g. Incidental prostate cancer was found in three patients (9%); one patient required adjuvant radiotherapy. No patients were catheter-dependent postoperatively; mean postvoid residual was 29 mL (range 0-250 mL). Median follow-up was 4 months. Conclusions: RASP-EP is a safe and efficacious technique that should form the repertoire of a urologist's armamentarium when dealing with large adenomas, particularly when entry into the peritoneal cavity is to be avoided. No competing financial interests exist. Runtime of video: 7 mins 5 secs.

Intravesical chemotherapy use after radical nephroureterectomy: A national survey of urologic oncologists.

To determine the use of prophylactic intravesical chemotherapy (pIVC) following radical nephroureterectomy (RNU) and barriers to utilization in a survey study of urologic oncologists. METHODS: A survey instrument was constructed, which queried respondents on professional experience, practice environment, pIVC use, and reasons for not recommending pIVC when applicable. The survey was electronically distributed to members of the Society of Urologic Oncology over an 8-week period. Survey software was used for analysis. RESULTS: The survey response rate was 22% (158 of 722). Half of the respondents were in practice for ≤10 years, while 90% performed ≤10 RNU cases annually. Of the 144 urologists regularly performing RNU, only 51% reported administering pIVC, including 22 exclusively in patients with a prior history of bladder cancer. One-third administered pIVC intraoperatively, whereas the remainder instilled pIVC at ≤3 (7%), 4 to 7 (37%), 8 to 14 (20%), and>14 (3%) days postoperatively. Almost all urologists noted giving a single instillation of pIVC. Agents included mitomycin-C (88%), thiotepa (7%), doxorubicin (3%), epirubicin (1%), and BCG (1%). Among respondents who did not administer pIVC, the most common reasons cited included lack of data supporting use (44%), personal preference (19%), and office infrastructure (17%). CONCLUSION: Only 51% of urologic oncologists report using pIVC in patients undergoing RNU. Reasons underlying this underutilization are multifactorial, thereby underscoring the need for continued dissemination of existing data and additional studies to support its benefits. Moreover, improving the logistics of pIVC administration may help to increase utilization rates.

Strategies for prevention of ultrasound-guided prostate biopsy infections.

Prostate cancer is the most common cancer in male patients and the second leading cause of cancer-related mortality in males. To confirm the diagnosis of prostate cancer, an ultrasound-guided needle biopsy is necessary to obtain prostate tissue sufficient for histologic analysis by pathologists. Ultrasound-guided prostate needle biopsy can be accomplished via a transperineal or transrectal approach. The latter biopsy technique involves placing an ultrasound probe into the rectum, visualizing the prostate located just anterior to it, and then obtaining 12-14 biopsies. Each biopsy core requires piercing of the rectal mucosa which can inherently contribute to infection. The increasing infectious risk of prostate needle biopsy requires refinement and re-evaluation of the process in which the technique is performed. Such processes include (but are not limited to) prebiopsy risk stratification, antibiotic prophylaxis, use of rectal preparations, and equipment processing. In the subsequent review, we highlight the current available information on different strategies to reduce the risk of infection following prostate needle biopsy.

Ceramide biogenesis is required for radiation-induced apoptosis in the germ line of C. elegans.

Ceramide engagement in apoptotic pathways has been a topic of controversy. To address this controversy, we tested loss-of-function (lf) mutants of conserved genes of sphingolipid metabolism in Caenorhabditis elegans. Although somatic (developmental) apoptosis was unaffected, ionizing radiation-induced apoptosis of germ cells was obliterated upon inactivation of ceramide synthase and restored upon microinjection of long-chain natural ceramide. Radiation-induced increase in the concentration of ceramide localized to mitochondria and was required for BH3-domain protein EGL-1-mediated displacement of CED-4 (an APAF-1-like protein) from the CED-9 (a Bcl-2 family member)/CED-4 complex, an obligate step in activation of the CED-3 caspase. These studies define CEP-1 (the worm homolog of the tumor suppressor p53)-mediated accumulation of EGL-1 and ceramide synthase-mediated generation of ceramide through parallel pathways that integrate at mitochondrial membranes to regulate stress-induced apoptosis.

REST and its corepressors mediate plasticity of neuronal gene chromatin throughout neurogenesis.

Regulation of neuronal gene expression is critical to central nervous system development. Here, we show that REST regulates the transitions from pluripotent to neural stem/progenitor cell and from progenitor to mature neuron. In the transition to progenitor cell, REST is degraded to levels just sufficient to maintain neuronal gene chromatin in an inactive state that is nonetheless poised for expression. As progenitors differentiate into neurons, REST and its co-repressors dissociate from the RE1 site, triggering activation of neuronal genes. In some genes, the level of expression is adjusted further in neurons by CoREST/MeCP2 repressor complexes that remain bound to a site of methylated DNA distinct from the RE1 site. Expression profiling based on this mechanism indicates that REST defines a gene set subject to plasticity in mature neurons. Thus, a multistage repressor mechanism controls the orderly expression of genes during development while still permitting fine tuning in response to specific stimuli.