Combination therapy strategies for improving PD-1 blockade efficacy: a new era in cancer immunotherapy.

Programmed death 1 (PD-1) is an immune checkpoint molecule that negatively regulates T-cell immune function through the interaction with its ligand PD-L1. Blockage of this interaction unleashes the immune system to fight cancer. Immunotherapy using PD-1 blockade has led to a paradigm shift in the field of cancer drug discovery, owing to its durable effect against a wide variety of cancers with limited adverse effects. A brief history and development of PD-1 blockade, from the initial discovery of PD-1 to the recent clinical output of this therapy, have been summarized here. Despite its tremendous clinical success rate over other cancer treatments, PD-1 blockade has its own pitfall; a significant fraction of patients remains unresponsive to this therapy. The key to improve the PD-1 blockade therapy is the development of combination therapies. As this approach has garnered worldwide interest, here, we have summarized the recent trends in the development of PD-1 blockade-based combination therapies and the ongoing clinical trials. These include combinations with checkpoint inhibitors, radiation therapy, chemotherapy and several other existing cancer treatments. Importantly, FDA has approved PD-1 blockade agent to be used in combination with either CTLA-4 blockade or chemotherapy. Responsiveness to the PD-1 blockade therapy is affected by tumour and immune system-related factors. The role of the immune system, especially T cells, in determining the responsiveness has been poorly studied compared with those factors related to the tumour side. Energy metabolism has emerged as one of the important regulatory mechanisms for the function and differentiation of T cells. We have documented here the recent results regarding the augmentation of PD-1 blockade efficacy by augmenting mitochondrial energy metabolism of T cell.

Ischemic Preconditioning Enhances Muscle Endurance during Sustained Isometric Exercise.

Ischemic preconditioning (IPC) enhances whole-body exercise endurance. However, it is poorly understood whether the beneficial effects originate from systemic (e. g., cardiovascular system) or peripheral (e. g., skeletal muscle) adaptations. The present study examined the effects of IPC on local muscle endurance during fatiguing isometric exercise. 12 male subjects performed sustained isometric unilateral knee-extension exercise at 20% of maximal voluntary contraction until failure. Prior to the exercise, subjects completed IPC or control (CON) treatments. During exercise trial, electromyography activity and near-infrared spectroscopy-derived deoxygenation in skeletal muscle were continuously recorded. Endurance time to task failure was significantly longer in IPC than in CON (mean±SE; 233±9 vs. 198±9 s, P<0.001). Quadriceps electromyography activity was not significantly different between IPC and CON. In contrast, deoxygenation dynamics in the quadriceps vastus lateralis muscle was significantly faster in IPC than in CON (27.1±3.4 vs. 35.0±3.6 s, P<0.01). The present study found that IPC can enhance muscular endurance during fatiguing isometric exercise. Moreover, IPC accelerated muscle deoxygenation dynamics during the exercise. Therefore, we suggest that the origin of beneficial effects of IPC on exercise performance may be the enhanced mitochondrial metabolism in skeletal muscle.

Field test of quantum key distribution in the Tokyo QKD Network.

A secure communication network with quantum key distribution in a metropolitan area is reported. Six different QKD systems are integrated into a mesh-type network. GHz-clocked QKD links enable us to demonstrate the world-first secure TV conferencing over a distance of 45km. The network includes a commercial QKD product for long-term stable operation, and application interface to secure mobile phones. Detection of an eavesdropper, rerouting into a secure path, and key relay via trusted nodes are demonstrated in this network.

High-rate quantum key distribution over 100 km using ultra-low-noise, 2-GHz sinusoidally gated InGaAs/InP avalanche photodiodes.

We have demonstrated quantum key distribution (QKD) over 100 km using single-photon detectors based on InGaAs/InP avalanche photodiodes (APDs). We implemented the differential phase shift QKD (DPS-QKD) protocol with electrically cooled and 2-GHz sinusoidally gated APDs. The single-photon detector has a dark count probability of 2.8 × 10(-8) (55 counts per second) with a detection efficiency of 6 %, which enabled us to achieve 24 kbit/s secure key rate over 100 km of optical fiber. The DPS-QKD system offers better performances in a practical way than those achieved using superconducting single-photon detectors. Moreover, the distance that secure keys against the general individual attacks can be distributed has been extended to 160 km.

AID-induced T-lymphoma or B-leukemia/lymphoma in a mouse BMT model.

Activation-induced cytidine deaminase (AID) diversifies immunoglobulin through somatic hypermutation (SHM) and class-switch recombination (CSR). AID-transgenic mice develop T-lymphoma, indicating that constitutive expression of AID leads to tumorigenesis. Here, we transplanted mouse bone marrow cells transduced with AID. Twenty-four of the 32 recipient mice developed T-lymphoma 2-4 months after the transplantation. Surprisingly, unlike AID-transgenic mice, seven recipients developed B-leukemia/lymphoma with longer latencies. None of the mice suffered from myeloid leukemia. When we used nude mice as recipients, they developed only B-leukemia/lymphoma, presumably due to lack of thymus. Analysis of AID mutants suggested that an intact form with SHM activity is required for maximum ability of AID to induce lymphoma. Except for a K-ras active mutant in one case, specific mutations could not be identified in T-lymphoma; however, Notch1 was constitutively activated in most cases. Importantly, truncations of Ebf1 or Pax5 were observed in B-leukemia/lymphoma. In conclusion, this is the first report on the potential of AID overexpression to promote B-cell lymphomagenesis in a mouse model. Aberrant expression of AID in bone marrow cells induced leukemia/lymphoma in a cell-lineage-dependent manner, mainly through its function as a mutator.

Effect of glimepiride and nateglinide on serum insulin and glucose concentration in healthy cats.

Glimepiride and nateglinide are two common oral hypoglycemic agents currently being used with humans suffering from Type 2 diabetes mellitus. Neither drug has been tested with cats thus far and it is currently unknown whether either of these drugs exert any effect in cats or not. The objective of this study was to determine the effect of glimepiride and nateglinide on glucose and insulin responses in healthy control cats, in order to determine their potential use in diabetic cats. The intravenous glucose tolerance tests was carried out since it is an excellent test for evaluating pancreatic beta-cell function for insulin secretion. Alterations in the insulin secretion pattern can be perceived as the earliest sign of beta-cell dysfunction in many species, including cats. Nateglinide demonstrated a quick action/short duration type effect with serum glucose nadiring and insulin response peaking at 60 and 20 minutes, respectively. Alternatively, glimepiride is medium-to-long acting with serum glucose nadiring and insulin response peaking at 180 minutes and 60 minutes, respectively. Nateglinide's potency was evident allowing it to induce a 1.5-2 higher preliminary insulin peak (3.7 +/- 1.1 pg/ml) than glimepiride's (2.5 +/- 0.1 pg/ml), albeit only for a short period of time. Because glimepiride and nateglinide have a shared mode of action, no significant differences in overall glucose AUC(0-360 min) (24,435 +/- 2,940 versus 24,782 +/- 2,354 mg min/dl) and insulin AUC(0-360 min) (410 +/- 192 versus 460 +/- 159) in healthy control cats were observed. These findings may provide useful information when choosing a hypoglycemic drug suited for the treatment of diabetic cats depending on the degree of diabetes mellitus the cat is suffering from.

Efficient entanglement distribution over 200 kilometers.

Here we report the first demonstration of entanglement distribution over a record distance of 200 km which is of sufficient fidelity to realize secure communication. In contrast to previous entanglement distribution schemes, we use detection elements based on practical avalanche photodiodes (APDs) operating in a self-differencing mode. These APDs are low-cost, compact and easy to operate requiring only electrical cooling to achieve high single photon detection efficiency. The self-differencing APDs in combination with a reliable parametric down-conversion source demonstrate that entanglement distribution over ultra-long distances has become both possible and practical. Consequently the outlook is extremely promising for real world entanglement-based communication between distantly separated parties.

Comparison of three commercially available prescription diet regimens on short-term post-prandial serum glucose and insulin concentrations in healthy cats.

Dietary therapy is an important treatment component for diabetes mellitus (DM). In this study, the impact of three different commercially available diet regiments (1 general use and 2 aimed for treating obesity and DM) on short-term post-prandial serum glucose and insulin concentrations of five healthy cats to better understand what impact each of these diets may have for diabetic cats. The diet regiments used in this study were as follows: C/D dry (General Use- Low protein, High fat, High carbohydrate, and Low fiber), M/D dry (DM- High protein, High fat, Low carbohydrate, and High Fiber), and W/D dry (DM- Low Protein, Low Fat, High Carbohydrate, and High Fiber). No significant difference in post-prandial serum glucose levels were observed with the C/D (84.6 +/- 1.5 mg/dl) and W/D (83.8 +/- 1.4 mg/dl) dry diets when compared to pre-prandial fasting levels (83.9 +/- 1.4 mg/dl). However, a significant reduction was observed with the M/D diet (78.9 +/- 0.8 mg/dl) which had 50-60% less carbohydrates than either C/D or W/D diet. Unlike what was observed with post-prandial glucose levels, an interesting pattern emerged with post-prandial insulin levels, which were increasing with W/D, C/D, and M/D diets in that order (1.1 +/- 0.2, 1.7 +/- 0.2, and 2.3 +/- 0.2 ng/ml respectively). Most surprising, though, was the fact that the W/D diet did not seem to stimulate insulin secretion as compared to pre-prandial levels (1.1 +/- 0.1 ng/ml) in healthy cats. Interestingly, the W/D diet had high levels of carbohydrate and low levels of protein. Coincidentally, the only diet (M/D) which had a significant reduction in post-prandial glucose also showed the highest increase in post-prandial insulin in healthy cats. Therefore, dietary amounts of carbohydrate, fat, protein and fiber can all have an individual impact on post-prandial glycemia and subsequent insulin requirement levels. Just as concepts regarding dietary management of people with DM are evolving, investigators are reassessing what constitutes the ideal diet for the diabetic feline. As such, having a better understanding for each dietary component, may lead us to better understand how we can synergize certain dietary components to aid in DM management.

A novel mouse model of hepatocarcinogenesis triggered by AID causing deleterious p53 mutations.

Activation-induced cytidine deaminase (AID), the only enzyme that is known to be able to induce mutations in the human genome, is required for somatic hypermutation and class-switch recombination in B lymphocytes. Recently, we showed that AID is implicated in the pathogenesis of human cancers including hepatitis C virus (HCV)-induced human hepatocellular carcinoma (HCC). In this study, we established a new AID transgenic mouse model (TNAP-AID) in which AID is expressed in cells producing tissue-nonspecific alkaline phosphatase (TNAP), which is a marker of primordial germ cells and immature stem cells, including ES cells. High expression of TNAP was found in the liver of the embryos and adults of TNAP-AID mice. HCC developed in 27% of these mice at the age of approximately 90 weeks. The HCC that developed in TNAP-AID mice expressed alpha-fetoprotein and had deleterious mutations in the tumour suppressor gene Trp53, some of which corresponded to those found in human cancer. In conclusion, TNAP-AID is a mouse model that spontaneously develops HCC, sharing genetic and phenotypic features with human HCC, which develops in the inflamed liver as a result of the accumulation of genetic changes.

Differential-phase-shift quantum secret sharing.

A quantum secret sharing (QSS) protocol based on a differential-phase-shift scheme is proposed, which quantum mechanically provides a full secret key to one party and partial keys to two other parties. A weak coherent pulse train is utilized instead of individual photons as in conventional schemes. Compared with previous QSS protocols, the present one features a simple setup, is suitable for fiber transmission, and offers the possibility for a high key creation rate. An experiment is also carried out to demonstrate the operation.

Efficient and low-noise single-photon detection in 1550 nm communication band by frequency upconversion in periodically poled LiNbO3 waveguides.

We demonstrate 1500 nm band single-photon detection with low dark-count noise and a potentially high efficiency, which may allow long distance and high-bit-rate quantum key distribution. By developing frequency upconversion devices based on periodically poled lithium niobate waveguides, which are specifically designed to use a pump wavelength longer than that of communication-band photons, we completely eliminate the dark-count noise caused by parasitic nonlinear processes in the waveguide. We observed an internal conversion efficiency as high as 40% and demonstrated scaling down to the single photon level while maintaining a background dark-count rate of 10(2)s(-1).

Long-distance entanglement-based quantum key distribution over optical fiber.

We report the first entanglement-based quantum key distribution (QKD) experiment over a 100-km optical fiber. We used superconducting single photon detectors based on NbN nanowires that provide high-speed single photon detection for the 1.5-mum telecom band, an efficient entangled photon pair source that consists of a fiber coupled periodically poled lithium niobate waveguide and ultra low loss filters, and planar lightwave circuit Mach-Zehnder interferometers (MZIs) with ultra stable operation. These characteristics enabled us to perform an entanglement-based QKD experiment over a 100-km optical fiber. In the experiment, which lasted approximately 8 hours, we successfully generated a 16 kbit sifted key with a quantum bit error rate of 6.9 % at a rate of 0.59 bits per second, from which we were able to distill a 3.9 kbit secure key.

Expression of activation-induced cytidine deaminase in human hepatocytes via NF-kappaB signaling.

Activation-induced cytidine deaminase (AID) is involved in somatic DNA alterations of the immunoglobulin gene for amplification of immune diversity. The fact that constitutive expression of AID in mice causes tumors in various organs, including lymphoid tissues and lungs, suggests the important role of the aberrant editing activity of AID on various tumor-related genes for carcinogenesis. AID expression, however, is restricted to activated B cells under physiological conditions. We demonstrate here that ectopic AID expression is induced in response to tumor necrosis factor-alpha stimulation in cultured human hepatocytes. The proinflammatory cytokine-mediated expression of AID is achieved by IkappaB kinase-dependent nuclear factor (NF)-kappaB signaling pathways. Hepatitis C virus, one of the leading causes of hepatocellular carcinoma (HCC), enhanced AID expression via NF-kappaB activation through expression of viral core protein. The aberrant expression of AID in hepatoma-derived cells resulted in accumulation of genetic alterations in the c-myc and pim1 genes, suggesting that inappropriate expression of AID acts as a DNA mutator that enhances the genetic susceptibility to mutagenesis in human hepatocytes. Our current findings indicate that the inappropriate expression of AID is induced by proinflammatory cytokine stimulation and may provide the link between hepatic inflammation and the development of HCC.

Generation of energy-time entangled photon pairs in 1.5-mum band with periodically poled lithium niobate waveguide.

We report the generation of 1.5-mm-band energy-time entangled photon pairs using a periodically poled lithium niobate (PPLN) waveguide. We performed a two-photon interference experiment and obtained coincidence fringes with 77.3% visibilities without subtracting accidental coincidences.

Long-distance distribution of time-bin entangled photon pairs over 100 km using frequency up-conversion detectors.

We report an experimental demonstration of the distribution of time-bin entangled photon pairs over 100 km of optical fiber. In our experiment, 1.5-mum non-degenerated time-bin entangled photon pairs were generated with a periodically poled lithium niobate (PPLN) waveguide by using the parametric down conversion process. Combining this approach with ultra-low-loss filters to eliminate the pump light and separate signal and idler photons, we obtained an efficient entangled photon pair source. To detect the photons, we used single-photon detectors based on frequency up-conversion. These detectors operated in a non-gated mode so that we could use a pulse stream of time correlated entangled photon pairs at a high repetition frequency (1 GHz). Using these elements, we distributed time-bin entangled photon pairs over 100 km of dispersion shifted fiber and performed a two-photon interference experiment. We obtained a coincidence fringe of 81.6% visibility without subtracting any background noise, such as accidental coincidence or dark count, which was good enough to violate Bell's inequality. Thus, we successfully distributed time-bin entangled photon pairs over 100 km.

Field trial of differential-phase-shift quantum key distribution using polarization independent frequency up-conversion detectors.

We report a field trial of differential phase shift quantum key distribution (QKD) using polarization independent frequency up-conversion detectors. A frequency up-conversion detector is a promising device for achieving a high key generation rate when combined with a high clock rate QKD system. However, its polarization dependence prevents it from being applied to practical QKD systems. In this paper, we employ a modified polarization diversity configuration to eliminate the polarization dependence. Applying this method, we performed a long-term stability test using a 17.6-km installed fiber. We successfully demonstrated stable operation for 6 hours and achieved a sifted key generation rate of 120 kbps and an average quantum bit error rate of 3.14 %. The sifted key generation rate was not the estimated value but the effective value, which means that the sifted key was continuously generated at a rate of 120 kbps for 6 hours.

Subtype IV of the BK polyomavirus is prevalent in East Asia.

BK polyomavirus (BKV) is ubiquitous in human populations, infecting children asymptomatically and then persisting in the kidney. Using either serological or genotyping methods, BKV isolates have been classified into four subtypes (I-IV), with subtype I mainly detected in all countries studied so far. To elucidate the subtype of BKV prevalent in East Asia, we examined BKV-positive urine samples collected from immunocompetent elderly patients in Mongolia, Northeast China, Northwest China, Southeast China, Southwest China, Vietnam and Japan. The 287-bp typing region of the viral genome in each of these samples was PCR-amplified and sequenced, and a phylogenetic tree was constructed. According to the tree, BKV isolates in East Asia were unambiguously classified into subtype I or IV (subtypes II and III were not detected). In Japan, subtype I was mainly detected and subtype IV was rare, whereas in the other regions subtype IV was detected frequently, at rates ranging from 24 to 100%. Thus, East Asia (excluding Japan) is a region in which subtype-IV BKV is prevalent, a finding that requires the view of the geographic distribution of BKV subtypes to be revised. Furthermore, we present evidence that the immunological states of urine donors do not affect the pattern of BKV subtypes.

Differential-phase-shift quantum key distribution experiment with a planar light-wave circuit Mach-Zehnder interferometer.

A differential-phase-shift quantum key distribution experiment was carried out with a planar light-wave circuit (PLC) Mach-Zehnder interferometer. This scheme has two advantages: it requires no polarization control and has a high repetition frequency, provided that a stable interferometer is available. Stable polarization-insensitive operation was achieved with an interferometer fabricated by PLC technology. Raw key creation at a rate of 3076 bits/s with a 5.0% quantum bit-error rate was achieved over 20 km of fiber. The stability of the PLC interferometer was examined.

Birth of offspring following transplantation of cryopreserved immature testicular pieces and in-vitro microinsemination.

BACKGROUND: Fertility protection is an urgent clinical problem for prepubertal male oncology patients who undergo either chemotherapy or radiotherapy. As these patients do not have mature sperm to be frozen, there is as yet no effective method to preserve their fertility. METHODS AND RESULTS: Single pieces of immature mouse (1.5 x 1.5 x 1.5 mm) or rabbit (2.0 x 2.0 x approximately 3.0 mm) testis were cryopreserved, thawed and transplanted into mouse testes. Histological techniques were used to determine the presence of spermatogenesis, which was restored in both mouse and rabbit testicular pieces, and led to the production of mature sperm after both cryopreservation and syngeneic or xenogeneic transplantation into mouse testes. Using sperm developed in the frozen-thawed transplants, mouse offspring were born after in-vitro microinsemination. Furthermore, rabbit offspring were obtained using rabbit sperm that developed in fresh transplants in a xenogeneic surrogate mouse. CONCLUSIONS: This approach of 'testicular tissue banking' is a promising technique for the preservation of fertility in prepubertal male oncology patients. Xenogeneic transplantation into immunodeficient mice may provide a system for studying spermatogenic failure in infertile men.

Asian domains of four major genotypes of JC virus, Af2, B1-b, CY and SC.

JC virus (JCV) strains worldwide can be classified into various genotypes based on DNA sequence variations. To define the domains of the four major JCV genotypes in Asia, we collected urine samples at six unstudied sites: three in southeastern Asia, two in the central highlands and one in central Asia. DNA was extracted from urine samples, and used to amplify a 610-bp region of the viral genome. For each geographical site, we determined 16 to 31 sequences, from which a phylogenetic tree was constructed to unambiguously classify detected JCV isolates into distinct genotypes. From JCV genotype profiles at the sites studied here and elsewhere, the following conclusions were drawn. Although Af2 is the major genotype in Africa, this genotype also occurs in western and central Asia. B1-b mainly occurs in western and central Asia, including the central highlands. CY occurs in northeastern Asia with the southern boundary between China and southeast Asian countries. Although SC predominates in southeastern Asia, it also occurs in northern and central Asia at lower frequencies. In addition, a few minor JCV genotypes (B1-a, B2 and B3) occur at many sites. We discuss here the anthropological and medical significance of the present findings.