Spatial firing of hippocampal place cells varies depending on the animal’s behavior relative to its goals. Here, rats were trained to approach visually guided reward ports in a two-dimensional open ...field. Hippocampal place cells encoded two independent pieces of information, spatial representation and goal-directed representation, by amplifying firing rates within their place fields specifically while the animal was moving toward a specific goal location. Irrespective of running speed and direction, substantial place-selective firing was observed that sustained a basal spatial map independent of goal-directed signals. When animals were allowed to freely forage in the field, in-field firing rates similarly increased when the animals transiently ran toward remembered goal locations. Disruption of medial septal activity significantly decreased goal-directed firing while maintaining spatial representation patterns. The findings indicate that the integrated encoding of spatial and goal-directed signals by hippocampal circuits is crucial for flexible spatial navigation to a goal location.
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•In-field firing rates of hippocampal cells increase during goal-directed behavior•Internally motivated goal-directed behavior boosts in-field firing•Medial septal inactivation reduces goal-directed firing
Aoki et al. find that firing rates of CA1 neurons increase when rats are running toward a goal location irrespective of the positional relationship between their place fields and goal location. The results suggest possible neurophysiological mechanisms for encoding place-selective and goal-directed signals by a hippocampal cell.
Epitaxial growth of silicene on atomically flat ultra-thin Ag(111) films was investigated using scanning tunneling microscopy. The Ag films were prepared by low-temperature deposition of Ag on Si ...substrates, followed by soft annealing at room temperature. Patchy 4 × 4, √13 × √13, √7 × √7, and 2√3 × 2√3 silicene domains were nucleated on regions that were one monolayer lower than the pristine Ag surface after the initial morphological change had been completed. On the first-layer silicene containing the above domains, two types of √3 × √3 silicene domains (√3 × √3- and ) were formed in the second layer. A bias voltage-independent Moiré pattern was observed for the √3 × √3- silicene, and a bias voltage-dependent standing wave pattern for the √3 × √3- silicene. The √3 × √3- silicene had a dispersion relation that could be fitted using a linear function, although the resulting Fermi velocity was twice as large as the expected value.
Cancer stem cells have been proposed to be important for initiation, maintenance and recurrence of various malignancies, including acute myeloid leukemia (AML). We have previously reported that ...CD34+CD38− human primary AML stem cells residing in the endosteal region of the bone marrow are relatively chemotherapy resistant. Using a NOD/SCID/IL2rγnull mouse model of human AML, we now show that the AML stem cells in the endosteal region are cell cycle quiescent and that these stem cells can be induced to enter the cell cycle by treatment with granulocyte colony-stimulating factor (G-CSF). In combination with cell cycle-dependent chemotherapy, G-CSF treatment significantly enhances induction of apoptosis and elimination of human primary AML stem cells in vivo. The combination therapy leads to significantly increased survival of secondary recipients after transplantation of leukemia cells compared with chemotherapy alone.
Background
The survival of patients with high‐risk, refractory, relapsed, or metastatic solid tumors remains dismal. A poly(ADP‐ribose) polymerase (PARP) inhibitor could be effective for the ...treatment of pediatric solid tumors with defective homologous recombination.
Methods
This open‐label, multicenter phase 1 clinical trial evaluated the safety, tolerability, and efficacy of olaparib, a PARP inhibitor, in pediatric patients with refractory solid tumors to recommend a dose for Phase 2 trials. Olaparib (62.5, 125, and 187.5 mg/m2 twice daily) was administered orally every day (1 cycle = 28 days) using a standard 3 + 3 dose‐escalation design. Patients aged 3–18 years with recurrent pediatric solid tumors were eligible. Pharmacokinetic and pharmacodynamic analyses were performed.
Results
Fifteen patients were enrolled and received olaparib monotherapy, which was well tolerated. The recommended phase 2 dose for daily administration was 187.5 mg/m2 twice daily. Pharmacokinetics were dose proportional. The area under the concentration‐time curve from 0 to 12 h and the peak plasma concentration for 187.5 mg/m2 twice daily in children were comparable to previous data obtained in a 200‐mg, twice‐daily cohort and lower than those in the 300‐mg twice‐daily cohort in adults. Pharmacodynamic studies demonstrated substantial inhibition of PARP activity. Two partial responses were observed in patients with Wilms tumor and neuroblastoma.
Conclusions
This report is the first clinical trial to describe the use of a PARP inhibitor as monotherapy in children. Olaparib was well tolerated, with preliminary antitumor responses observed in DNA damage response‐defective pediatric tumors.
Lay summary
This Phase 1 trial evaluated the efficacy and safety of olaparib in patients with refractory childhood solid tumors.
Olaparib was well tolerated, achieving objective response in 2/15 patients.
The DNA damage response was attenuated in nearly one‐half of advanced neuroblastoma patients, demonstrating the utility of the PARP inhibitor.
The results support further investigation of olaparib as a new treatment for DNA damage‐response or repair‐defective pediatric cancers.
This report is the first clinical trial to describe the use of a poly(ADP‐ribose) polymerase inhibitor as monotherapy in children. Olaparib was well tolerated, with preliminary antitumor responses observed in DNA damage response–defective pediatric tumors.
Obturator hernia is a rare condition that commonly affects frail older women. A 54-year-old woman presented to our hospital with left hip joint pain. She had suffered a left pubic bone fracture and ...commenced maintenance hemodialysis. Pelvic computed tomography (CT) showed an incarcerated small intestine through the left obturator foramen, while abdominal CT showed marked intestinal dilatation. She underwent emergency laparotomy, and the incarcerated small intestine was found to be necrotic. Partial small intestinal resection and bilateral obturator hernioplasty were performed. Because obturator hernia is a potentially fatal condition, early detection and treatment are important.
The Ewing sarcoma breakpoint region 1 (EWSR1) gene is known to fuse with various partner genes to promote the development of the Ewing sarcoma family of tumors and other sarcomas. In contrast, the ...association of EWSR1 chimeric fusion genes with leukemia has rarely been reported. We identified a novel EWSR1‐associated chimeric fusion gene in a patient with acute myeloid leukemia harboring 46, XY, t (11; 22) (p13; q12) karyotype abnormality. The patient was refractory to intensified chemotherapy including hematopoietic stem cell transplantation. Total RNA paired‐end sequencing identified a novel chimeric fusion gene as EWSR1/ELF5, a member of the E26 transformation‐specific transcription factor family. Transduction of EWSR1/ELF5 to NIH3T3 cells induced transformation by attenuating with the p53/p21‐dependent pathway. The injection of EWSR1/ELF5‐transduced NIH3T3 cells into NSG‐SCID mice systematically induced the development of tumors in vivo. These results revealed the oncogenic potency of EWSR1/ELF5.
Novel chimeric fusion gene, EWSR1/ELF5, was identified in a patient with acute myeloid leukemia (AML). EWSR1/ELF5 induced cetllular transformation by attenuating with the p53/p21‐dependent pathway.
Obturator hernia is a rare condition that commonly affects frail older women. A 54-year-old woman presented to our hospital with left hip joint pain. She had suffered a left pubic bone fracture and ...commenced maintenance hemodialysis. Pelvic computed tomography (CT) showed an incarcerated small intestine through the left obturator foramen, while abdominal CT showed marked intestinal dilatation. She underwent emergency laparotomy, and the incarcerated small intestine was found to be necrotic. Partial small intestinal resection and bilateral obturator hernioplasty were performed. Because obturator hernia is a potentially fatal condition, early detection and treatment are important.
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