We present GOseq, an application for performing Gene Ontology (GO) analysis on RNA-seq data. GO analysis is widely used to reduce complexity and highlight biological processes in genome-wide ...expression studies, but standard methods give biased results on RNA-seq data due to over-detection of differential expression for long and highly expressed transcripts. Application of GOseq to a prostate cancer data set shows that GOseq dramatically changes the results, highlighting categories more consistent with the known biology.
The immune system can identify and destroy nascent tumor cells in a process termed cancer immunosurveillance, which functions as an important defense against cancer. Recently, data obtained from ...numerous investigations in mouse models of cancer and in humans with cancer offer compelling evidence that particular innate and adaptive immune cell types, effector molecules, and pathways can sometimes collectively function as extrinsic tumor-suppressor mechanisms. However, the immune system can also promote tumor progression. Together, the dual host-protective and tumor-promoting actions of immunity are referred to as cancer immunoediting. In this review, we discuss the current experimental and human clinical data supporting a cancer immunoediting process that provide the fundamental basis for further study of immunity to cancer and for the rational design of immunotherapies against cancer.
Resting state functional connectivity is defined in terms of temporal correlations between physiologic signals, most commonly studied using functional magnetic resonance imaging. Major features of ...functional connectivity correspond to structural (axonal) connectivity. However, this relation is not one-to-one. Interhemispheric functional connectivity in relation to the corpus callosum presents a case in point. Specifically, several reports have documented nearly intact interhemispheric functional connectivity in individuals in whom the corpus callosum (the major commissure between the hemispheres) never develops. To investigate this question, we assessed functional connectivity before and after surgical section of the corpus callosum in 22 patients with medically refractory epilepsy. Section of the corpus callosum markedly reduced interhemispheric functional connectivity. This effect was more profound in multimodal associative areas in the frontal and parietal lobe than primary regions of sensorimotor and visual function. Moreover, no evidence of recovery was observed in a limited sample in which multiyear, longitudinal follow-up was obtained. Comparison of partial vs. complete callosotomy revealed several effects implying the existence of polysynaptic functional connectivity between remote brain regions. Thus, our results demonstrate that callosal as well as extracallosal anatomical connections play a role in the maintenance of interhemispheric functional connectivity.
Spontaneous fluctuations in the blood-oxygen-level-dependent (BOLD) signals demonstrate consistent temporal correlations within large-scale brain networks associated with different functions. The ...neurophysiological correlates of this phenomenon remain elusive. Here, we show in humans that the slow cortical potentials recorded by electrocorticography demonstrate a correlation structure similar to that of spontaneous BOLD fluctuations across wakefulness, slow-wave sleep, and rapid-eye-movement sleep. Gamma frequency power also showed a similar correlation structure but only during wakefulness and rapid-eye-movement sleep. Our results provide an important bridge between the large-scale brain networks readily revealed by spontaneous BOLD signals and their underlying neurophysiology.
Cancer immunoediting, the process by which the immune system controls tumour outgrowth and shapes tumour immunogenicity, is comprised of three phases: elimination, equilibrium and escape. Although ...many immune components that participate in this process are known, its underlying mechanisms remain poorly defined. A central tenet of cancer immunoediting is that T-cell recognition of tumour antigens drives the immunological destruction or sculpting of a developing cancer. However, our current understanding of tumour antigens comes largely from analyses of cancers that develop in immunocompetent hosts and thus may have already been edited. Little is known about the antigens expressed in nascent tumour cells, whether they are sufficient to induce protective antitumour immune responses or whether their expression is modulated by the immune system. Here, using massively parallel sequencing, we characterize expressed mutations in highly immunogenic methylcholanthrene-induced sarcomas derived from immunodeficient Rag2(-/-) mice that phenotypically resemble nascent primary tumour cells. Using class I prediction algorithms, we identify mutant spectrin-β2 as a potential rejection antigen of the d42m1 sarcoma and validate this prediction by conventional antigen expression cloning and detection. We also demonstrate that cancer immunoediting of d42m1 occurs via a T-cell-dependent immunoselection process that promotes outgrowth of pre-existing tumour cell clones lacking highly antigenic mutant spectrin-β2 and other potential strong antigens. These results demonstrate that the strong immunogenicity of an unedited tumour can be ascribed to expression of highly antigenic mutant proteins and show that outgrowth of tumour cells that lack these strong antigens via a T-cell-dependent immunoselection process represents one mechanism of cancer immunoediting.
Abstract
BACKGROUND:
Corpus callosotomy (CC) is a valuable palliative surgical option for children with medically refractory epilepsy due to generalized or multifocal cortical seizure onset.
...OBJECTIVE:
To investigate the extent of CC resulting in optimal seizure control in a pediatric patient population and to evaluate the modification of seizure profile after various CC approaches.
METHODS:
The records of 58 children (3–22 years of age at the time of surgery) with medically refractory epilepsy who underwent CC between 1995 and 2011 were retrospectively reviewed.
RESULTS:
Anterior two thirds callosotomy resulted in resolution of absence (P = .03) and astatic (P = .03) seizures, whereas anterior two thirds callosotomy followed by second-stage completion resulted in resolution of generalized tonic-clonic (GTC) (P = .03), astatic (P = .005), and myoclonic (P = .03) seizures in addition to a trend toward resolution of absence seizures (P = .08). Single-stage upfront complete callosotomy resulted in resolution of absence (P = .002), astatic (P < .0001), myoclonic (P = .007), and complex partial (P = .008) seizures in addition to a trend toward resolution of GTC (P = .06). In comparing a composite of subjects who underwent anterior two thirds callosotomy alone or 2-stage complete callosotomy before the second stage to complete the callosotomy with subjects who underwent upfront complete CC, a more favorable outcome was found in those with the upfront complete CC (P = .02).
CONCLUSION:
Single-stage upfront complete callosotomy is effective in relieving a broader spectrum of seizure types than anterior two thirds callosotomy or 2-stage complete callosotomy in children. The advantages of single-stage complete callosotomy must be weighed against the potentially higher risk of neurological and operative complications.
Corpus callosotomy is a palliative procedure that is effective at reducing seizure burden in patients with medically refractory epilepsy. The procedure is traditionally performed via open craniotomy ...with interhemispheric microdissection to divide the corpus callosum. Concerns for morbidity associated with craniotomy can be a deterrent to patients, families, and referring physicians for surgical treatment of epilepsy. Laser interstitial thermal therapy (LITT) is a less invasive procedure that has been widely adopted in neurosurgery for the treatment of tumors. In this study, the authors investigated LITT as a less invasive approach for corpus callosotomy.
The authors retrospectively reviewed all patients treated for medically refractory epilepsy by corpus callosotomy, either partial or completion, with LITT. Chart records were analyzed to summarize procedural metrics, length of stay, adverse events, seizure outcomes, and time to follow-up. In select cases, resting-state functional MRI was performed to qualitatively support effective functional disconnection of the cerebral hemispheres.
Ten patients underwent 11 LITT procedures. Five patients received an anterior two-thirds LITT callosotomy as their first procedure. One patient returned after LITT partial callosotomy for completion of callosotomy by LITT. The median hospital stay was 2 days (IQR 1.5-3 days), and the mean follow-up time was 1.0 year (range 1 month to 2.86 years). Functional outcomes are similar to those of open callosotomy, with the greatest effect in patients with a significant component of drop attacks in their seizure semiology. One patient achieved an Engel class II outcome after anterior two-thirds callosotomy resulting in only rare seizures at the 18-month follow-up. Four others were in Engel class III and 5 were Engel class IV. Hemorrhage occurred in 1 patient at the time of removal of the laser fiber, which was placed through the bone flap of a prior open partial callosotomy.
LITT appears to be a safe and effective means for performing corpus callosotomy. Additional data are needed to confirm equipoise between open craniotomy and LITT for corpus callosotomy.
Here we report the effects of loss of the Toll-like receptor-associated signaling adaptor myeloid-differentiation factor 88 (MyD88) on tumor induction in two distinct mouse models of carcinogenesis. ...The 7,12-dimethylbenzaanthracene (DMBA)/12-O-tetradecanoylphorbol 13-acetate (TPA)-induced skin papilloma model depends on proinflammatory processes, whereas the 3'-methylcholanthrene (MCA) induction of fibrosarcoma has been used by tumor immunologists to illustrate innate and adaptive immune surveillance of cancer. When exposed to a combination of DMBA/TPA, mice lacking MyD88 formed fewer skin papillomas than genetically matched WT controls treated in a similar manner. Unexpectedly, however, fewer MyD88⁻/⁻ mice formed sarcomas than WT controls when exposed to MCA. In contrast, MyD88-deficient mice did not show a defective ability to reject highly immunogenic transplanted tumors, including MCA sarcomas. Despite the reported role of TNF in chronic inflammation, TNF-deficient mice were significantly more susceptible to MCA-induced sarcoma than WT mice. Overall, these data not only confirm the key role that MyD88 plays in promoting tumor development but also demonstrate that inflammation-induced carcinogenesis and cancer immunoediting can indeed occur in the same mouse tumor model.
Summary
Corpus callosotomy is a palliative surgical procedure for patients with refractory epilepsy. It can be performed through an open approach via a standard craniotomy and the aid of an operating ...microscope, or alternatively via a mini‐craniotomy with endoscope assistance. The extent of callosal disconnection performed varies according to indications and surgeon preference. In this article, we describe both open and endoscopic surgical techniques for anterior and complete corpus callosotomy.
One of the most intriguing recent discoveries concerning brain function is that intrinsic neuronal activity manifests as spontaneous fluctuations of the blood oxygen level-dependent (BOLD) functional ...MRI signal. These BOLD fluctuations exhibit temporal synchrony within widely distributed brain regions known as resting-state networks. Resting-state networks are present in the waking state, during sleep, and under general anesthesia, suggesting that spontaneous neuronal activity plays a fundamental role in brain function. Despite its ubiquitous presence, the physiological role of correlated, spontaneous neuronal activity remains poorly understood. One hypothesis is that this activity is critical for the development of synaptic connections and maintenance of synaptic homeostasis. We had a unique opportunity to test this hypothesis in a 5-y-old boy with severe epileptic encephalopathy. The child developed marked neurologic dysfunction in association with a seizure disorder, resulting in a 1-y period of behavioral regression and progressive loss of developmental milestones. His EEG showed a markedly abnormal pattern of high-amplitude, disorganized slow activity with frequent generalized and multifocal epileptiform discharges. Resting-state functional connectivity MRI showed reduced BOLD fluctuations and a pervasive lack of normal connectivity. The child underwent successful corpus callosotomy surgery for treatment of drop seizures. Postoperatively, the patient's behavior returned to baseline, and he resumed development of new skills. The waking EEG revealed a normal background, and functional connectivity MRI demonstrated restoration of functional connectivity architecture. These results provide evidence that intrinsic, coherent neuronal signaling may be essential to the development and maintenance of the brain's functional organization.
PDF
