Ablative Radiotherapy Reprograms the Tumor Microenvironment of a Pancreatic Tumor in Favoring the Immune Checkpoint Blockade Therapy

The low overall survival rate of patients with pancreatic cancer has driven research to seek a new therapeutic protocol. Radiotherapy (RT) is frequently an option in the neoadjuvant or palliative settings for pancreatic cancer treatment. This study explored the effect of RT protocols on the tumor microenvironment (TME) and their consequent impact on anti-programmed cell death ligand-1 (PD-L1) therapy. Using a murine orthotopic pancreatic tumor model, UN-KC-6141, RT-disturbed TME was examined by immunohistochemical staining. The results showed that ablative RT is more effective than fractionated RT at recruiting T cells. On the other hand, fractionated RT induces more myeloid-derived suppressor cell infiltration than ablative RT. The RT-disturbed TME presents a higher perfusion rate per vessel. The increase in vessel perfusion is associated with a higher amount of anti-PD-L1 antibody being delivered to the tumor. Animal survival is increased by anti-PD-L1 therapy after ablative RT, with 67% of treated animals surviving more than 30 days after tumor inoculation compared to a median survival time of 16.5 days for the control group. Splenocytes isolated from surviving animals were specifically cytotoxic for UN-KC-6141 cells. We conclude that the ablative RT-induced TME is more suited than conventional RT-induced TME to combination therapy with immune checkpoint blockade.     

Speed superiority of scaled double-gate CMOS

Unloaded ring-oscillator simulations, performed with a generic process/physics-based compact model for double-gate (DG) MOSFETs and supplemented with model-predicted on-state currents and gate capacitances for varying supply voltages (V_DD), are used to show and explain the speed superiority of extremely scaled DG CMOS over the single-gate (e.g., bulk-Si) counterpart. The DG superiority for unloaded circuits is most substantive for low V_DD < ~1 V     

Electrical stimulation of the medial prefrontal cortex increases dopamine release in the striatum

Exogenous and endogenous glutamate has been shown to evoke dopamine (DA) release in the striatum using both in vitro and in vivo techniques. We hypothesized that stimulation of the prefrontal cortex (PFC) would phasically enhance striatal DA release via the glutamatergic corticostriatal pathway. To test this hypothesis, in vivo brain microdialysis was employed to measure extracellular concentrations of DA in the striatum during electrical stimulation of the PFC. Five rats were implanted with bilateral electrodes located in the medial PFC and dialysis probes in the dorsal striatum. Two days later the PFC of these awake, freely moving rats was stimulated first at 50 microA and then at 100 microA for 20 minutes at 2-hour intervals. Both currents significantly increased DA release. Extracellular DA rose rapidly during stimulation, peaked immediately afterward, and then slowly returned to baseline values. Dopamine reached 118% of baseline values with 50 microA stimulation and 138% with 100 microA stimulation. Histologic analysis using the fluorescent retrograde dye Fluoro Gold confirmed that cells projecting to the vicinity of the striatal dialysis probe originated in the vicinity of the PFC electrodes. These results provide direct evidence for phasic, excitatory modulation of striatal DA release by the PFC.     

Efficient random subcloning of DNA sheared in a recirculating point-sink flow system

Based on a high-performance liquid chromatographic pump, we have built a device that allows recirculation of DNA through a 63-microm orifice with ensuing fractionation to a minimum fragment size of approximately 300 base pairs. Residence time of the DNA fragments in the converging flow created by a sudden contraction was found to be sufficiently long to allow extension of the DNA molecules into a highly extended conformation and, hence, breakage to occur at midpoint. In most instances, 30 passages sufficed to obtain a narrow size distribution, with >90% of the fragments lying within a 2-fold size distribution. The shear rate required to achieve breakage was found to be inversely proportional to the 1.0 power of the molecular weight. Compared with a restriction digest, up to 40% of all fragments could be cloned directly, with only marginal improvements in cloning efficiency having been observed upon prior end repair with Klenow, T4 polymerase or T4 polynucleotide kinase. Sequencing revealed a fairly random distribution of the fragments.     

The directional effects of passive eye movement on the directional visual responses of single units in the pigeon optic tectum

We have investigated the visual responses of 184 single units located in the superficial layers of the optic tectum (OT) of the decerebrate, paralysed pigeon. Visual responses were similar to those reported in non-decerebrate preparations; most units responded best to moving visual stimuli, 18% were directionally selective (they had a clear preference for a particular direction of visual stimulus movement), 76% were plane-selective (they responded to movement in either direction in a particular plane). However, we also found that a high proportion of units showed some sensitivity to the orientation of visual stimuli. We examined the effects of extraocular muscle (EOM) afferent signals, induced by passive eye movement (PEM), on the directional visual responses of units. Visual responses were most modified by particular directions of eye movement, although there was no unique relationship between the direction of visual stimulus movement to which an individual unit responded best and the direction of eye movement that caused the greatest modification of that visual response. The results show that EOM afferent signals, carrying information concerning the direction of eye movement, reach the superficial layers of the OT in the pigeon and there modify the visual responses of units in a manner that suggests some role for these signals in the processing of visual information.     

Treatment of hypertension in nondiabetic renal disease

To clarify whether long-term impaired glucose tolerance (IGT) is associated with dysfunction of peripheral and autonomic nerves, age-matched men with IGT and diabetes mellitus were followed prospectively for 12-15 years, when peripheral and autonomic nerve function was assessed. The patients comprised four subgroups: (1) 51 IGT subjects (duration of IGT at least 12-15 years); (2) 35 diabetic patients, with IGT 12-15 years ago, who later developed diabetes; (3) 34 diabetic patients, duration of diabetes at least 12-15 years; and (4) 62 age-matched non-diabetic control subjects. Mean age of the whole study population was 61 +/- 2 years (mean +/- SD), not different in the four groups. Peripheral nerve function tests included nerve conduction velocities, amplitudes, distal latencies, F-reflexes, and sensory perception thresholds for heat, cold, and vibration. Autonomic nerve function tests included the heart rate reaction during deep breathing (expiration to inspiration ratio) and to tilt (acceleration and brake indices). Despite 12-15 years of IGT, peripheral nerve function did not differ between IGT and control subjects, whereas autonomic nerve function deviated; an abnormal expiration to inspiration ratio (a sign of vagal nerve dysfunction) was significantly more common (15/51 versus 5/62; p < 0.01) in IGT than in control subjects. Diabetic patients (groups 2 and 3) showed lower conduction velocities (in general 2-4 m s-1 lower) than IGT and control subjects in all tested nerves. In conclusion, diabetes but not IGT, is associated with peripheral nerve dysfunction.     

Design criterion for low-loss optical coupler tapers

A criterion for the local taper angle of a low-loss single-mode fibre coupler is established by considering the dominant mode coupling in the coupler taper. Effects due to structure parameters, such as cladding/core thickness ratio, corecladding index difference and core separation, are investigated. It is found that the criterion for the coupler taper can be well approximated by that for the single-mode fibre taper with the same structure parameters.     

Channel capacity and state estimation for state-dependent Gaussian channels

We formulate a problem of state information transmission over a state-dependent channel with states known at the transmitter. In particular, we solve a problem of minimizing the mean-squared channel state estimation error E/spl par/S/sup n/ - S/spl circ//sup n//spl par/ for a state-dependent additive Gaussian channel Y/sup n/ = X/sup n/ + S/sup n/ + Z/sup n/ with an independent and identically distributed (i.i.d.) Gaussian state sequence S/sup n/ = (S/sub 1/, ..., S/sub n/) known at the transmitter and an unknown i.i.d. additive Gaussian noise Z/sup n/. We show that a simple technique of direct state amplification (i.e., X/sup n/ = /spl alpha/S/sup n/), where the transmitter uses its entire power budget to amplify the channel state, yields the minimum mean-squared state estimation error. This same channel can also be used to send additional independent information at the expense of a higher channel state estimation error. We characterize the optimal tradeoff between the rate R of the independent information that can be reliably transmitted and the mean-squared state estimation error D. We show that any optimal (R, D) tradeoff pair can be achieved via a simple power-sharing technique, whereby the transmitter power is appropriately allocated between pure information transmission and state amplification.