Background: Methods: Results: Conclusion:

Recent progress in atmospheric plasmas has led to the creation of cold plasmas with ion temperature close to room temperature. This paper outlines recent progress in understanding of cold plasma physics as well as application of cold atmospheric plasma (CAP) in cancer therapy. Varieties of novel plasma diagnostic techniques were developed recently in a quest to understand physics of CAP. It was established that the streamer head charge is about 108 electrons, the electrical field in the head vicinity is about 107 V/m, and the electron density of the streamer column is about 1019 m−3. Both in-vitro and in-vivo studies of CAP action on cancer were performed. It was shown that the cold plasma application selectively eradicates cancer cells in-vitro without damaging normal cells and significantly reduces tumor size in-vivo. Studies indicate that the mechanism of action of cold plasma on cancer cells is related to generation of reactive oxygen species with possible induction of the apoptosis pathway. It is also shown that the cancer cells are more susceptible to the effects of CAP because a greater percentage of cells are in the S phase of the cell cycle.

The survival rate among patients with intermediate-risk neuroblastoma who receive dose-intensive chemotherapy is excellent, but the survival rate among patients who receive reduced doses of chemotherapy for shorter periods of time is not known. We conducted a prospective, phase 3, nonrandomized trial to determine whether a 3-year estimated overall survival of more than 90% could be maintained with reductions in the duration of therapy and drug doses, using a tumor biology−based therapy assignment. Eligible patients had newly diagnosed, intermediate-risk neuroblastoma without MYCN amplification; these patients included infants (<365 days of age) who had stage 3 or 4 disease, children (≥365 days of age) who had stage 3 tumors with favorable histopathological features, and infants who had stage 4S disease with a diploid DNA index or unfavorable histopathological features. Patients who had disease with favorable histopathological features and hyperdiploidy were assigned to four cycles of chemotherapy, and those with an incomplete response or either unfavorable feature were assigned to eight cycles. Between 1997 and 2005, a total of 479 eligible patients were enrolled in this trial (270 patients with stage 3 disease, 178 with stage 4 disease, and 31 with stage 4S disease). A total of 323 patients had tumors with favorable biologic features, and 141 had tumors with unfavorable biologic features. Ploidy, but not histopathological features, was significantly predictive of the outcome. Severe adverse events without disease progression occurred in 10 patients (2.1%), including secondary leukemia (in 3 patients), death from infection (in 3 patients), and death at surgery (in 4 patients). The 3-year estimate (±SE) of overall survival for the entire group was 96±1%, with an overall survival rate of 98±1% among patients who had tumors with favorable biologic features and 93±2% among patients who had tumors with unfavorable biologic features. A very high rate of survival among patients with intermediate-risk neuroblastoma was achieved with a biologically based treatment assignment involving a substantially reduced duration of chemotherapy and reduced doses of chemotherapeutic agents as compared with the regimens used in earlier trials. These data provide support for further reduction in chemotherapy with more refined risk stratification. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00003093.)

We report an early onset spastic ataxia-neuropathy syndrome in two brothers of a consanguineous family characterized clinically by lower extremity spasticity, peripheral neuropathy, ptosis, oculomotor apraxia, dystonia, cerebellar atrophy, and progressive myoclonic epilepsy. Whole-exome sequencing identified a homozygous missense mutation (c.1847G>A; p.Y616C) in AFG3L2, encoding a subunit of an m-AAA protease. m-AAA proteases reside in the mitochondrial inner membrane and are responsible for removal of damaged or misfolded proteins and proteolytic activation of essential mitochondrial proteins. AFG3L2 forms either a homo-oligomeric isoenzyme or a hetero-oligomeric complex with paraplegin, a homologous protein mutated in hereditary spastic paraplegia type 7 (SPG7). Heterozygous loss-of-function mutations in AFG3L2 cause autosomal-dominant spinocerebellar ataxia type 28 (SCA28), a disorder whose phenotype is strikingly different from that of our patients. As defined in yeast complementation assays, the AFG3L2^Y616C gene product is a hypomorphic variant that exhibited oligomerization defects in yeast as well as in patient fibroblasts. Specifically, the formation of AFG3L2^Y616C complexes was impaired, both with itself and to a greater extent with paraplegin. This produced an early-onset clinical syndrome that combines the severe phenotypes of SPG7 and SCA28, in additional to other “mitochondrial” features such as oculomotor apraxia, extrapyramidal dysfunction, and myoclonic epilepsy. These findings expand the phenotype associated with AFG3L2 mutations and suggest that AFG3L2-related disease should be considered in the differential diagnosis of spastic ataxias. Mitochondria are cellular organelles important for converting sugar or fats into energy that cells can use for their functions and survival. Many neurological diseases are the result of mitochondrial dysfunction as affected cells are unable to cope with lowered energy supplies and increased oxidative stress. These deficiencies cause accumulation of cellular damage and eventually cell death. Spastic ataxias are neurological disorders involving cells with large energy requirements, the cerebellar Purkinje cells and the cerebral upper motor neurons. When these cells function improperly or die, individuals develop symptoms of incoordination (ataxia) and abnormal muscle tone in their legs (spastic paraplegia). Using emerging techniques of whole-exome sequencing we discovered that homozygous mutations in the AFG3L2 gene caused spastic ataxia in two brothers of a consanguineous family. AFG3L2 encodes a subunit of mitochondrial matrix proteases (m-AAA proteases) that regulate the functional integrity of mitochondria. Heterozygous mutations in AFG3L2 were previously found to cause a disorder involving the Purkinje cells of the cerebellum resulting in ataxia. Interestingly, another isoform of m-AAA proteases consists of AFG3L2 complexing with paraplegin, a similar protein associated with a hereditary spastic paraplegia. Our analysis provides insight into why different mutations in m-AAA protease subunits cause different neurological disorders.