Fred C. Lam

The bromodomain protein Brd4 insulates chromatin from DNA damage signalling

DNA damage activates a signalling network that blocks cell-cycle progression, recruits DNA repair factors and/or triggers senescence or programmed cell death. Alterations in chromatin structure are implicated in the initiation and propagation of the DNA damage response. Here we further investigate the role of chromatin structure in the DNA damage response by monitoring ionizing-radiation-induced signalling and response events with a high-content multiplex RNA-mediated interference screen of chromatin-modifying and -interacting genes. We discover that an isoform of Brd4, a bromodomain and extra-terminal (BET) family member, functions as an endogenous inhibitor of DNA damage response signalling by recruiting the condensin II chromatin remodelling complex to acetylated histones through bromodomain interactions. Loss of this isoform results in relaxed chromatin structure, rapid cell-cycle checkpoint recovery and enhanced survival after irradiation, whereas functional gain of this isoform compacted chromatin, attenuated DNA damage response signalling and enhanced radiation-induced lethality. These data implicate Brd4, previously known for its role in transcriptional control, as an insulator of chromatin that can modulate the signalling response to DNA damage.

The DNA-sensing AIM2 inflammasome controls radiation-induced cell death and tissue injury.

AIMing to block tissue damage Ionizing radiation kills actively dividing cells such as those in the gut and in the bone marrow. Hu et al. found a pathological role for the protein AIM2 in irradiation-induced tissue damage. AIM2 is best known for its role in sensing double-stranded DNA in the cytoplasm and alerting the body to infections. It seems that AIM2 also senses DNA damage caused by radiation and then triggers intestinal epithelial cells and bone marrow cells to die. Deficiency in AIM2 protected mice from irradiation-induced gastrointestinal syndrome and hematopoietic failure. Science, this issue p. 765 AIM2 detects radiation-induced DNA damage and triggers intestinal epithelial cell and bone marrow cell death. Acute exposure to ionizing radiation induces massive cell death and severe damage to tissues containing actively proliferating cells, including bone marrow and the gastrointestinal tract. However, the cellular and molecular mechanisms underlying this pathology remain controversial. Here, we show that mice deficient in the double-stranded DNA sensor AIM2 are protected from both subtotal body irradiation–induced gastrointestinal syndrome and total body irradiation–induced hematopoietic failure. AIM2 mediates the caspase-1–dependent death of intestinal epithelial cells and bone marrow cells in response to double-strand DNA breaks caused by ionizing radiation and chemotherapeutic agents. Mechanistically, we found that AIM2 senses radiation-induced DNA damage in the nucleus to mediate inflammasome activation and cell death. Our results suggest that AIM2 may be a new therapeutic target for ionizing radiation exposure.

Augmented autologous pericranium duraplasty in 100 posterior fossa surgeries--a retrospective case series.

BACKGROUND: Primary closure of the dura in posterior fossa (p-fossa) surgeries is technically difficult and usually requires the use of a dural substitute. A variety of substitutes are currently available and data suggest that autologous materials are preferred in comparison with nonautologous substitutes. OBJECTIVE: To report our experience using locally harvested autologous pericranium as a dural substitute in patients who underwent p-fossa surgeries. METHODS: Retrospective analysis of patients who had undergone p-fossa craniotomies between 2005 and 2011. All patients received locally harvested autologous pericranium for duraplasty augmented with a dural sealant. Data were reviewed for complications including: surgical site infection, meningitis, cerebrospinal fluid leak, the radiographic formation of a pseudomeningocele, and any new neurological symptoms related to the incision or repair. RESULTS: One hundred patients were identified. Indications for surgery included tumor, vascular lesions, or hemorrhage requiring surgical intervention, symptomatic Chiari I malformation, microvascular decompression for trigeminal neuralgia, and trauma requiring surgical decompression. The complication rate was 1% with 1 patient developing an nonsteroidal anti-inflammatory drug-induced aseptic meningitis and graft dehiscence requiring surgical revision. CONCLUSION: Autologous pericranium with dural sealant augmentation is an effective way to repair the durotomy in p-fossa surgeries. To the best of our knowledge, this is currently the largest study using this technique in the adult neurosurgical literature. Our results report a much lower rate of complications in comparison with other duraplasty studies. ABBREVIATIONS: IV, intravenously NSAID, nonsteroidal anti-inflammatory drug p-fossa, posterior fossa

Time is brain the Gifford factor - or: Why do some civilian gunshot wounds to the head do unexpectedly well? A case series with outcomes analysis and a management guide.

Background: Review of intracranial gunshot wounds (GSWs) undergoing emergent neurosurgical intervention despite a very low Glasgow Coma Scale (GCS) score on admission in order to identify predictors of good outcome, with correlates to recent literature. Methods: A retrospective review of select cases of GSWs presenting to our trauma center over the past 5 years with poor GCS requiring emergent neurosurgical intervention and a minimum of 1-year follow-up. Results: Out of a total of 17 patients who went to the operating room (OR) for GSW to the head during this period, 4 cases with a GCS < 5 on admission were identified. All cases required a hemicraniectomy to alleviate cerebral swelling. Two cases presented with a unilaterally blown pupil due to raised intracranial pressure. The remaining 2 cases had equal and reactive pupils. One patient with a GCS of 3 and a significant bilateral pattern of parenchymal bullet injury was initially assessed in moribund status but rallied and received a delayed hemicraniectomy on day 7. Three out of 4 patients are functionally independent at 1-year follow-up. The fourth patient who received a delayed decompression remains wheelchair dependent. Conclusion: Victims of GSWs can have good outcomes despite having a very poor admission GCS score and papillary abnormalities. Factors predicting good outcomes include the following: time from injury to surgical intervention of < 1 h; injury to noneloquent brain; and absence of injury to midbrain, brainstem, and major vessels.

The effects of design and positioning of carbon fiber lumbar interbody cages and their subsidence in vertebral bodies.

Study Design A biomechanical study using human cadaveric lumbar spines. Objectives To determine the strength and stiffness of 3 carbon fiber cage designs in axial compression. To assess the effects of bone mineral density (BMD) on vertebral endplate failure with respect to the different cage patterns. Summary of Background Data Unilateral transforaminal approaches are gaining popularity compared with posterolateral lumbar interbody fusion. With differences in the inherent strengths of each quadrant of the endplate, the effect of different cage designs and their location on the endplate may affect subsidence and fusion success. Methods BMD measurements were obtained from 30 human spinal segments from L3 to L5. Discectomies were performed and cages were placed on the cephalad endplate of each vertebra in 3 configurations: 2 small posterolateral rectangular cages; 1 small anterior banana cage; and 1 small central rectangular cage. Each segment was tested under compression until endplate failure was recorded. Two-way analysis of variance was used to test for the effects of cage design on cage subsidence and endplate failure. Analysis of covariance was conducted to test for the effects of age, BMD, and vertebral levels on the failure load and stiffness for each cage design. Results Cage design was not significant in affecting failure force across the endplate. There were insignificant differences comparing stiffness in compression for the 3 different cage placements patterns. Low BMD adversely affected failure force and construct stiffness across all 3 cage patterns. Conclusions Cage design and position do not significantly affect failure of the construct or stiffness in compression across the endplate. BMD significantly affects both failure forces and stiffness but is not dependent on the positioning or design of the cage.

Fibrin sealant augmentation with autologous pericranium for duraplasty after suboccipital decompression in Chiari 1 patients: A case series.

Background: The Chiari 1 malformation (CM1) involves decent of the tonsils of the cerebellum through the foramen magnum. Symptomatic disease requires a posterior fossa decompression with or without an expansile duraplasty. To date, the optimal surgical treatment for CM1 has not been delineated. The extent of bony removal, size of the dural opening, necessity for expansion of the dural space, choice of materials for the duraplasty, and possible need for augmentation with dural sealant are all factors that continue to be debated amongst neurological surgeons worldwide. We herein evaluate the use of fibrin sealant augmentation in combination with locally harvested autologous pericranium for duraplasty in adult CM1 decompression. Methods: Retrospective data collected from January 2006 to December 2011. Data were reviewed for surgical site infection or meningitis, cerebrospinal fluid leak, symptomatic pseudomeningocele, radiographic improvement of hindbrain compression, and postoperative recurrence of symptoms at a minimum of 1 year of follow-up. Outcomes were studied clinically, radiographically, as well as by using a patient-specific questionnaire. Results: Twenty-two consecutive patients were included. One patient required a revision for a delayed graft dehiscence in the setting of a rare form of aseptic meningitis with cerebrospinal fluid (CSF) pleocytosis due to a nonsteroidal anti-inflammatory drug (NSAID) allergy. All remaining patients had successful decompressions with full resolution of their symptoms except for one patient who had persistent headaches. Conclusion: Autologous pericranium with dural sealant augmentation is an effective technique for expansile duraplasty in CM1 decompressions.

Arteriovenous fistula and pseudoaneurysm of the anterior spinal artery caused by an epidural needle in a 5-year-old patient

Authors present the case of a 5-year-old patient with a spinal arteriovenous fistula (AVF) and pseudoaneurysm of the anterior spinal artery (ASA) caused by a traumatic epidural needle stick injury. A discussion and relevant review of the literature follow. The boy had a remote history of a liver transplant and required neuraxial blockade for an unrelated abdominal surgical procedure. Initial insertion of the epidural needle at the T9-10 interspace yielded blood. A second attempt at T10-11 was successful. Delayed left leg weakness developed on postoperative Day 8, with an MR image showing a track injury through the cord and a ventral subarachnoid hematoma. Laminectomies from T-9 to T-11were performed emergently to decompress the spinal cord. The dura mater was opened, the ventral hematoma was evacuated, and brisk venous bleeding was controlled with cauterization. Postoperative spinal angiography demonstrated an AVF and pseudoaneurysm of the ASA. Repeat angiography at postoperative Week 4 demonstrated complete resolution of the AVF and pseudoaneurysm, probably due to intraoperative cauterization of the draining vein. The patient underwent a short course of rehabilitation and had no clinical or electrophysiological evidence of spinal cord damage at the 20-month follow-up. One should be cognizant of the possibility of a cord injury in a patient with new-onset neurological deficits following an interventional spine procedure. Neuroimaging is essential for prompt diagnosis and treatment.

Hitting all the right markers to save a life Solitary fibrous tumors of the central nervous system: Case series and review of the literature.

Background: Solitary fibrous tumors (SFTs) of the central nervous system are uncommon. Their biological features remain largely unknown; hence, the clinical management and prognosis is often challenging due to the lack of comprehensive data. For this reason, we present two cases of large SFTs to illustrate a comprehensive review. Methods: This was a retrospective analysis of two patients: a 65-year-old male with a left parietooccipital lesion and a 70-year-old female with a right parietal convexity mass. Results: Gross total resection was performed in the male patient with no recurrence 30 months after resection. The second patient received stereotactic radiosurgery for what was initially thought to be a parafalcine meningioma; however, continued growth 1 year later prompted an open resection, with pathology indicative of an SFT. The tumor recurred the following year requiring repeat resection. Unfortunately, due to the aggressive nature of the lesion, the patient eventually succumbed to tumor burden a year later. Conclusion: Based on the literature review, the sometimes observed aggressive growth pattern, and also, the potential for malignant transformation, we recommend complete resection of SFTs with close sequential follow-up.

An anterior approach to spinal pathology of the upper thoracic spine through a partial manubriotomy

Surgical pathology in the region of the upper thoracic spine (T1-4) is uncommon compared with other regions of the spine. Often times posterior and posterolateral approaches can be used, but formal anterior decompression often requires a low anterior cervical approach combined with a sternotomy, which yields significant perioperative morbidity. The authors describe a modified low anterior cervical dissection combined with a partial manubriotomy that they have used to successfully access and decompress anterior pathology of the upper thoracic spine. Their modified approach spares the sternoclavicular joints and leaves the sternum intact, decreasing the morbidity associated with these added procedures.

Kicking Genomic Profiling to the Curb: How Re-wiring the Phosphoproteome Can Explain Treatment Resistance in Glioma.

In this issue of Cancer Cell, Wei et al. (2016) identify adaptive re-wiring of signaling nodes in glioma as major mechanisms of treatment resistance without genome-wide mutations. Targeting these nodes before treatment blocks resistance and underscores the importance of single-cell phosphoproteomics and network re-wiring in predicting cancer treatment responses.