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The usefulness of the derived neutrophil-to-lymphocyte ratio (dNLR) and its dynamics before/after durvalumab consolidation therapy to predict safety or efficacy remains unclear. We retrospectively reviewed patients with locally advanced non-small cell lung cancer treated with durvalumab consolidation therapy after chemoradiotherapy (D group) or chemoradiotherapy alone (non-D group) at multiple institutions. We investigated the association between dNLR, or its dynamics, and pneumonitis, checkpoint inhibitor-related pneumonitis (CIP), irAEs, and efficacy. Ninety-eight and fifty-six patients were enrolled in the D and non-D groups, respectively. The dNLR at baseline was significantly lower in patients who experienced irAEs or CIP than in those who did not. The low dNLR group, 28 days following durvalumab consolidation therapy (dNLR28 ≤ 3), demonstrated longer progression-free survival (PFS) and overall survival (OS) than the high dNLR group (dNLR28 > 3) (PFS, hazard ratio [HR] 0.44, 95% confidence interval [CI] 0.22-0.88, p = 0.020; OS, HR 0.39, 95% CI 0.16-0.94, p = 0.037). Among patients with high dNLR at baseline (dNLR > 3), the dNLR28 ≤ 3 group showed longer PFS than the dNLR28 > 3 group (p = 0.010). The dNLR is a predictive factor for irAEs and CIP in patients receiving durvalumab consolidation therapy. The dNLR at 28 days after durvalumab consolidation therapy and its dynamics predict favorable outcomes., (© 2024. The Author(s).)

Invasive Anoplophora glabripennis recently became established in Japan and has caused heavy damage to several street-tree species. Overseas, A. glabripennis infests trees of the genera Acer and Populus as common host plants, and Malus, Pyrus, and Prunus (Rosaceae), including apple, pear, and plum trees; it therefore poses a potential risk to the production of economically valuable fruits in Japan. Fruit farms in areas already invaded by A. glabripennis are now threatened with tree infestation. We aimed to determine the potential damage to major fruit species in Japan. In the laboratory, we determined if the adult beetle is attracted to the odor of each of these tree species' branches; two confirmed host plant species and five Rosaceae fruit species, as well as its feeding preferences among branches of one host plant and the five fruit trees and its oviposition preferences among them. Among the fruit species, cherry branch had the highest rate of odor orientation by males. The feeding-preference assay showed that, besides the host plant, Japanese pear was the most consumed among the fruit trees. The potential risk of A. glabripennis laying eggs on fruit-tree branches was high for Japanese pear and above zero for plum, apple, and cherry branches., (© 2024. The Author(s).)

Continued receipt of Renin-Angiotensin-Aldosterone inhibitors in patients with COVID-19 has shown potential in producing better clinical outcomes. However, superiority between ACEi (angiotensin-converting enzyme inhibitors) and ARB (angiotensin II receptor blockers) regarding clinical outcomes in this setting remains unknown. We retrospectively collected data on patients hospitalized for acute COVID-19 using the nationwide administrative database (Diagnosis and Procedure Combinations, DPC). The DPC data covered around 25% of all acute care hospitals in Japan. Patient outcomes, with focus on inpatient mortality, were compared between patients previously prescribed ACEi and those prescribed ARB. Comparisons based on crude, multivariate and propensity-score adjusted analysis were conducted. We examined a total of 7613 patients (ARB group, 6903; ACEi group 710). The ARB group showed lower crude in-hospital mortality, compared to the ACEi group (5% vs 8%; odds ratio, 0.65; 95% CI 0.48-0.87), however not in the multivariate-adjusted model (odds ratio, 0.95; 95% CI 0.69-1.3) or propensity-score adjusted models (odds ratio, 0.86; 95% CI 0.63-1.2). ARB shows potential in reducing hospital stay duration over ACEi in patients admitted for COVID-19, but does not significantly reduce in-hospital mortality. Further prospective studies are needed to draw a definitive conclusion, but continuation of either of these medications is warranted to improve clinical outcomes., (© 2023. The Author(s).)

Given the constraints of both overseas development aid and domestic financing for nutrition, innovative financing is critical-yet nutrition lags behind other sectors in catalysing it. Here, we argue that the framing for nutrition must evolve and critical actions must be taken to generate more money for nutrition and more nutrition for money. Food systems hold some of the most powerful opportunities to improve human and planetary health while increasing productivity-and the private sector has a key role to play in this., (© 2023. Springer Nature Limited.)

COVID-19 is a viral infection and does not require antibiotics. The study aimed to elucidate a prescribing pattern of antibiotics for COVID-19. A nationwide cross-sectional study was conducted in Japan. The Diagnosis and Procedure Combinations (DPC) data was used to collect information, covering 25% of all acute care hospitals in the country. In 140,439 COVID-19 patients, 18,550 (13.21%) patients received antibiotics. Antibiotics were prescribed more often in inpatients (10,809 out of 66,912, 16.15%) than outpatients (7741 out of 73,527, 10.53%) (p < 0.001). Outpatient prescription was significantly associated with older patients (odds ratio [OR], 4.66; 95% confidence interval [CI] 4.41-4.93) and a greater Charlson index (OR with one-point index increase, 1.22; 95% CI 1.21-1.23). Inpatient prescription was significantly associated with older patients (OR 2.10; 95% CI 2.01-2.21), male gender (OR 1.12, 95% CI 1.07-1.18), a greater Charlson index (OR with one-point increase, 1.06; 95% CI 1.05-1.07), requirement of oxygen therapy (OR 3.44; 95% CI 3.28-3.60) and mechanical ventilation (OR 15.09; 95% CI 13.60-16.74). The most frequently prescribed antibiotic among outpatients was cefazolin, while that among inpatients was ceftriaxone. Antibiotic prescription is relatively low for acute COVID-19 in Japan. Antibiotic prescription was associated with older age, multi-morbidity, severe disease, and winter season., (© 2022. The Author(s).)

To reveal waning humoral immunity after second dose BNT162b2 vaccinations in a rural Japanese community and determine factors affecting antibody titers. We aimed to report Immunoglobulin G (IgG) antibody against the SARS-CoV-2 spike (S1) protein levels and neutralizing activity in a large scale community based cohort., Methods: Participants in the observational cross-sectional study received a second dose of vaccination with BNT162b2 (Pfizer/BioNTech) and were not previously infected with COVID-19. Questionnaire-collected data on sex, age, adverse vaccine reactions, and medical history was obtained., Results: Data from 2496 participants revealed that older age groups reached a low antibody titer 90-120 days after the second vaccination. Neutralizing activity decreased with age; 35 (13.3%) of those aged ≥ 80 years had neutralizing activity under the cut-off value. Neutralizing activity > 179 days from the second vaccination was 11.6% compared to that at < 60 days from the second vaccination. Significantly lower IgG antibody titers and neutralizing activity were associated with age, male sex, increased time from second vaccination, smoking, steroids, immunosuppression, and comorbidities., Conclusions: Antibody titer decreased substantially over time. Susceptible populations, older people, men, smokers, steroid users, immunosuppression users, and people with three or more comorbidities may require a special protection strategy., (© 2022. The Author(s).)

Elucidating the risk factors for chronic kidney disease is important for preventing end-stage renal disease and reducing mortality. However, little is known about the roles of psychosocial stress and stress coping behaviors in deterioration of the renal function, as measured by the estimated glomerular filtration rate (eGFR). This cross-sectional study of middle-aged and older Japanese men (n = 31,703) and women (n = 38,939) investigated whether perceived stress and coping strategies (emotional expression, emotional support seeking, positive reappraisal, problem solving, and disengagement) were related to the eGFR, with mutual interactions. In multiple linear regression analyses adjusted for age, area, lifestyle factors, and psychosocial variables, we found a significant inverse association between perceived stress and the eGFR in men (P trend  = 0.02), but not women. This male-specific inverse association was slightly attenuated after adjustment for the history of hypertension and diabetes and was more evident in lower levels of emotional expression (P interaction  = 0.003). Unexpectedly, problem solving in men (P trend  < 0.001) and positive reappraisal in women (P trend  = 0.002) also showed an inverse association with the eGFR. Perceived stress may affect the eGFR, partly through the development of hypertension and diabetes. The unexpected findings regarding coping strategies require the clarification of the underlying mechanisms, including the hormonal and immunological aspects., (© 2022. The Author(s).)

Leptin is an adipocyte-derived hormone that regulates appetite and energy expenditure via the hypothalamus. Since the majority of obese subjects are leptin resistant, leptin sensitizers, rather than leptin itself, are expected to be anti-obesity drugs. Endoplasmic reticulum (ER) stress in the hypothalamus plays a key role in the pathogenesis of leptin resistance. ATP-deficient cells are vulnerable to ER stress and ATP treatment protects cells against ER stress. Thus, we investigated the therapeutic effects of oral 1,3-butanediol (BD) administration, which increases plasma β-hydroxybutyrate and hypothalamic ATP concentrations, in diet induced obese (DIO) mice with leptin resistance. BD treatment effectively decreased food intake and body weight in DIO mice. In contrast, BD treatment had no effect in leptin deficient ob/ob mice. Co-administration experiment demonstrated that BD treatment sensitizes leptin action in both DIO and ob/ob mice. We also demonstrated that BD treatment attenuates ER stress and leptin resistance at the hypothalamus level. This is the first report to confirm the leptin sensitizing effect of BD treatment in leptin resistant DIO mice. The present study provides collateral evidence suggesting that the effect of BD treatment is mediated by the elevation of hypothalamic ATP concentration. Ketone bodies and hypothalamic ATP are the potential target for the treatment of obesity and its complications., (© 2021. The Author(s).)

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are well-recognised as an extended disease spectrum. This study hypothesised that cortical hyperexcitability, an early pathophysiological abnormality in ALS, would distinguish cognitive phenotypes, as a surrogate marker of pathological disease burden. 61 patients with ALS, matched for disease duration (pure motor ALS, n = 39; ALS with coexistent FTD, ALS-FTD, n = 12; ALS with cognitive/behavioural abnormalities not meeting FTD criteria, ALS-Cog, n = 10) and 30 age-matched healthy controls. Cognitive function on the Addenbrooke's cognitive examination (ACE) scale, behavioural function on the motor neuron disease behavior scale (MiND-B) and cortical excitability using transcranial magnetic stimulation (TMS) were documented. Cortical resting motor threshold (RMT), lower threshold indicating hyperexcitability, was lower in ALS-FTD (50.2 ± 6.9) compared to controls (64.3 ± 12.6, p < 0.005), while ALS-Cog (63.3 ± 12.7) and ALS (60.8 ± 13.9, not significant) were similar to controls. Short interval intracortical inhibition (SICI) was reduced across all ALS groups compared to controls, indicating hyperexcitability. On receiver operating characteristic curve analysis, RMT differentiated ALS-FTD from ALS (area under the curve AUC = 0.745, p = 0.011). The present study has identified a distinct pattern of cortical excitability across cognitive phenotypes in ALS. As such, assessment of cortical physiology may provide more precise clinical prognostication in ALS.

Gastrointestinal colonization has been considered as the primary source of candidaemia; however, few established mouse models are available that mimic this infection route. We therefore developed a reproducible mouse model of invasive candidiasis initiated by fungal translocation and compared the virulence of six major pathogenic Candida species. The mice were fed a low-protein diet and then inoculated intragastrically with Candida cells. Oral antibiotics and cyclophosphamide were then administered to facilitate colonization and subsequent dissemination of Candida cells. Mice infected with Candida albicans and Candida tropicalis exhibited higher mortality than mice infected with the other four species. Among the less virulent species, stool titres of Candida glabrata and Candida parapsilosis were higher than those of Candida krusei and Candida guilliermondii. The fungal burdens of C. parapsilosis and C. krusei in the livers and kidneys were significantly greater than those of C. guilliermondii. Histopathologically, C. albicans demonstrated the highest pathogenicity to invade into gut mucosa and liver tissues causing marked necrosis. Overall, this model allowed analysis of the virulence traits of Candida strains in individual mice including colonization in the gut, penetration into intestinal mucosa, invasion into blood vessels, and the subsequent dissemination leading to lethal infections.

Colorectal cancer demonstrates intra-tumour heterogeneity formed by a hierarchical structure comprised of cancer stem cells (CSCs) and their differentiated progenies. The mechanism by which CSCs are maintained and differentiated needs to be further elucidated, and there is evidence that the tumour microenvironment governs cancer stemness. Using PLR123, a colon cancer cell line with CSC properties, we determined the culture conditions necessary to establish a pair of three-dimensional (3D) culture models grown in Matrigel, designated stemCO and diffCO. The conditions were determined by comparing the phenotypes in the models with PLR123 mouse xenografts colonising lung and liver. StemCO resembled LGR5-positive undifferentiated tumours in the lung, and diffCO had lumen structures composed of polarised cells that were similar to the ductal structures found in differentiated tumours in the liver. In a case using the models for biomedical research, treatment with JAG-1 peptide or a γ-secretase inhibitor modified the Notch signaling and induced changes indicating that the signal participates in lumen formation in the models. Our results demonstrate that culture conditions affect the stemness of 3D culture models generated from CSCs and show that comparing models with different phenotypes is useful for studying how the tumour environment regulates cancer.

Mouse peritoneal macrophages consist of two subsets: large peritoneal macrophages (LPMs) and small peritoneal macrophages (SPMs), defined as CD11b hi F4/80 hi and CD11b + F4/80 lo cells, respectively. We reveal that SPMs, but not LPMs, have the ability to present antigens to naïve CD4 + T cells. Coculture of SPMs with naïve ovalbumin (OVA) specific CD4 + T cells (OT-II) in the presence of OVA peptide effectively induced CD4 + T cells priming. SPMs, but not LPMs, strongly express DNAM-1, an activating immunoreceptor. Although antigen uptake and processing were comparable between WT and DNAM-1-deficient SPMs, deficiency of DNAM-1 on SPMs or blockade of DNAM-1 and its ligand interaction impaired CD4 + T cells priming by SPMs. Furthermore, T and B cell responses in mediastinal lymph nodes of mice intraperitoneally immunized with trinitrophenyl (TNP)-OVA protein in Alum adjuvant were enhanced by intraperitoneally transferred wild-type, but not DNAM-1-deficient, SPMs. We propose that SPMs are functionally distinct from LPMs, and DNAM-1 plays a costimulatory role in antigen presentation by SPMs.

Over 80% of perinatal mortality in Japan is due to stillbirths after 22 weeks of gestation, with one in 300 families experiencing fetal loss every year. This study aimed to assess causes and risk factors for singleton stillbirth in Japan. A retrospective cross-sectional study was conducted using the Japan Society of Obstetrics and Gynecology Perinatal Database from January 2013 to December 2014. A total of 379,211 births including 2,133 stillbirths were analyzed. Causes of death were classified into eight categories. A multi-level Poisson regression model was used to assess the relationship between stillbirth and key covariates. Causes of death were unknown in 25-40% of stillbirths across gestational age. Placental abnormality accounted for the largest proportion of known causes, followed by umbilical cord abnormality. Stillbirth risk was increased among small-for-gestational-age infants (adjusted relative risk [ARR]: 3.78, 95% confidence interval [CI]: 3.31-4.32) and nulliparous women (ARR: 1.19, 95% CI: 1.05-1.35). Maternal underweight, pregnancy-induced hypertension and oligohydramnios showed a protective effect. Our finding suggests that stillbirths occurring among women with known complications are likely already being prevented. Further reduction in stillbirths must target small-sized fetuses and nulliparous women. Improved recording of the causal pathways of stillbirths is also needed.

As Japan has achieved one of the lowest perinatal mortality rates (PMR), our study aims to estimate trends in and risk factors for perinatal mortality among singleton births in Japan. We used Japanese vital registration data to assess trends in and risk factors for perinatal outcomes between 1979 and 2010. Birth and death registration data were merged. An autoregressive integrated moving average model was fitted separately by sex to the PMR and the proportion of stillbirths. A multilevel Poisson regression model was used to estimate risk factors for perinatal mortality. Between 1979 and 2010 there were 40,833,957 pregnancies and 355,193 perinatal deaths, the PMR decreased from 18.86 per 1,000 all births to 3.25 per 1,000 all births, and the proportion of stillbirths increased from 83.6% to 92.1%. Key risk factors for perinatal mortality were low or high birth weight, prematurity and post maturity, and being from poorer or unemployed families. A higher proportion of excess perinatal deaths could be averted by effective policies to prevent stillbirths and improved research into their interventions and risk factors. As the cost and challenge of maintaining perinatal mortality gains increases, policies need to be targeted towards higher risk groups and social determinants of health.

We investigated the lethal effects of visible light on insects by using light-emitting diodes (LEDs). The toxic effects of ultraviolet (UV) light, particularly shortwave (i.e., UVB and UVC) light, on organisms are well known. However, the effects of irradiation with visible light remain unclear, although shorter wavelengths are known to be more lethal. Irradiation with visible light is not thought to cause mortality in complex animals including insects. Here, however, we found that irradiation with short-wavelength visible (blue) light killed eggs, larvae, pupae, and adults of Drosophila melanogaster. Blue light was also lethal to mosquitoes and flour beetles, but the effective wavelength at which mortality occurred differed among the insect species. Our findings suggest that highly toxic wavelengths of visible light are species-specific in insects, and that shorter wavelengths are not always more toxic. For some animals, such as insects, blue light is more harmful than UV light.

In the classic transistor, the number of electric charge carriers--and thus the electrical conductivity--is precisely controlled by external voltage, providing electrical switching capability. This simple but powerful feature is essential for information processing technology, and also provides a platform for fundamental physics research. As the number of charges essentially determines the electronic phase of a condensed-matter system, transistor operation enables reversible and isothermal changes in the system's state, as successfully demonstrated in electric-field-induced ferromagnetism and superconductivity. However, this effect of the electric field is limited to a channel thickness of nanometres or less, owing to the presence of Thomas-Fermi screening. Here we show that this conventional picture does not apply to a class of materials characterized by inherent collective interactions between electrons and the crystal lattice. We prepared metal-insulator-semiconductor field-effect transistors based on vanadium dioxide--a strongly correlated material with a thermally driven, first-order metal-insulator transition well above room temperature--and found that electrostatic charging at a surface drives all the previously localized charge carriers in the bulk material into motion, leading to the emergence of a three-dimensional metallic ground state. This non-local switching of the electronic state is achieved by applying a voltage of only about one volt. In a voltage-sweep measurement, the first-order nature of the metal-insulator transition provides a non-volatile memory effect, which is operable at room temperature. Our results demonstrate a conceptually new field-effect device, extending the concept of electric-field control to macroscopic phase control.

Control of the stem-like tumour cell population is considered key to realizing the long-term survival of patients with glioblastoma, one of the most devastating human malignancies. To date, possible therapeutic targets and targeting methods have been described, but none has yet proven to target stem-like glioblastoma cells in the brain to the extent necessary to provide a survival benefit. Here we show that targeting JNK in vivo, the activity of which is required for the maintenance of stem-like glioblastoma cells, via transient, systemic administration of a small-molecule JNK inhibitor depletes the self-renewing and tumour-initiating populations within established tumours, inhibits tumour formation by stem-like glioblastoma cells in the brain, and provide substantial survival benefit without evidence of adverse events. Our findings not only implicate JNK in the maintenance of stem-like glioblastoma cells but also demonstrate that JNK is a viable, clinically relevant therapeutic target in the control of stem-like glioblastoma cells.

Human solid tumors contain hypoxic regions that have considerably lower oxygen tension than the normal tissues. Hypoxia offers resistance to radiotherapy and anticancer chemotherapy, as well as predispose to increased tumor metastases. Furthermore, hypoxia induces hypoxia-inducible factor-1 (HIF-1), which in turn increases tumor angiogenesis. Thus, eradication of HIF-1-active/hypoxic tumor cells is very important for cancer therapy. We have previously reported that procaspase-3 fused with a von Hippel-Lindau (VHL)-mediated protein destruction motif of alpha subunit of HIF-1 (HIF-1alpha) containing Pro564, named TAT-ODD-procaspase-3 (TOP3), specifically induced cell death to hypoxic cells in vivo as well as in vitro. We now report that TOP3 also eradicates the radiation-induced HIF-1-active tumor cells. HIF-1 activity in the xenografts of human tumor cells, which express luciferase under the transcriptional control of HIF-1, were monitored and quantified daily with an in vivo bioluminescence photon-counting device. HIF-1 activity in tumors was more rapidly increased by ionizing radiation (IR) compared to untreated tumors. TOP3 efficiently decreased the HIF-1-activity in irradiated tumors as well as unirradiated ones, indicating TOP3 eradicated tumor cells with HIF-1-activity induced by IR as well as hypoxia. Eradication of HIF-1-active/hypoxic cells in the xenografts during irradiation exhibited significant suppression in angiogenesis and strong enhancement in a long-term growth suppression of tumor xenografts. These results further strengthen the argument that HIF-1-active/hypoxic cells play crucial roles in angiogenesis and radioresistance.

Correlated oxides display a variety of extraordinary physical properties including high-temperature superconductivity and colossal magnetoresistance. In these materials, strong electronic correlations often lead to competing ground states that are sensitive to many parameters--in particular the doping level--so that complex phase diagrams are observed. A flexible way to explore the role of doping is to tune the electron or hole concentration with electric fields, as is done in standard semiconductor field effect transistors. Here we demonstrate a model oxide system based on high-quality heterostructures in which the ferroelectric field effect approach can be studied. We use a single-crystal film of the perovskite superconductor Nb-doped SrTiO3 as the superconducting channel and ferroelectric Pb(Zr,Ti)O3 as the gate oxide. Atomic force microscopy is used to locally reverse the ferroelectric polarization, thus inducing large resistivity and carrier modulations, resulting in a clear shift in the superconducting critical temperature. Field-induced switching from the normal state to the (zero resistance) superconducting state was achieved at a well-defined temperature. This unique system could lead to a field of research in which devices are realized by locally defining in the same material superconducting and normal regions with 'perfect' interfaces, the interface being purely electronic. Using this approach, one could potentially design one-dimensional superconducting wires, superconducting rings and junctions, superconducting quantum interference devices (SQUIDs) or arrays of pinning centres.

Estimates of the disease burden caused by malaria are crucial for informing malaria control programmes. Snow and colleagues claim that their estimate of 515 million cases of malaria caused by Plasmodium falciparum globally is up to 50% higher than that reported by the World Health Organization (WHO), and 200% higher for areas outside Africa. However, this comparison refers to the WHO's estimates from 1990 and 1998, and not to the range of 300 million to 500 million that the WHO has used since 2000 (ref. 2). Both groups agree that the burden of malaria disease outside Africa, especially in South Asia, is greater than was estimated in the 1990s.

The human genome is by far the largest genome to be sequenced, and its size and complexity present many challenges for sequence assembly. The International Human Genome Sequencing Consortium constructed a map of the whole genome to enable the selection of clones for sequencing and for the accurate assembly of the genome sequence. Here we report the construction of the whole-genome bacterial artificial chromosome (BAC) map and its integration with previous landmark maps and information from mapping efforts focused on specific chromosomal regions. We also describe the integration of sequence data with the map.

We examined whether pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) is capable of improving thrombocytopenia and promoting thrombopoietic reconstitution following lethal irradiation and bone marrow transplantation (BMT) in mice. Immediately after receiving 10 Gy whole body irradiation (day 0), male C3H/HeN mice were inoculated with 10(6) bone marrow cells obtained from syngeneic mice. Circulating platelet counts decreased to below 4% of the normal counts with a nadir on day 10, and then returned to the normal level on day 28 in the control mice undergoing BMT. Subcutaneous consecutive treatment with PEG-rHuMGDF at doses from 10 to 300 micrograms/kg/day from day 1 for 13 days significantly improved the platelet nadir and promoted platelet recovery. The white blood cell counts and hemoglobin concentration following BMT were not influenced by the PEG-rHuMGDF. PEG-rHuMGDF-injection starting from day 5 did not improve the platelet nadir following BMT. Furthermore, administration with PEG-rHuMGDF on alternate days at 55.7 micrograms/kg/day for 7 days or at an interval of 3 days at 78 micrograms/kg/day for 4 days (twice a week for 2 weeks) had a significant efficacy, but these administration regimens had less efficacy than consecutive administration at 30 micrograms/kg/day for 13 days. The numbers of megakaryocytes and megakaryocyte progenitor cells decreased to 5 and 0.2% of normal level, respectively, in the control mice. Consecutive administration of PEG-rHuMGDF enhanced the recovery of the mean number of these cells compared to those in vehicle-treated mice, although such effects were not statistically significant except for the number of megakaryocyte progenitors on day 12. These results suggest that consecutive treatment with PEG-rHuMGDF beginning from the day after BMT may be effective in improving thrombocytopenia following BMT.

Interleukin-2 is an autocrine growth factor for T cells which also activates other cells including B cells and natural killer cells. The subunits of the interleukin-2 receptor (IL-2R) lack intrinsic enzymatic activity, but protein tyrosine phosphorylation is a critical event following ligand binding and src family kinases, such as Lck, are known to be activated by IL-2 (refs 5-9). However, IL-2 signalling can occur in the absence of receptor interaction with Lck, suggesting that other protein tyrosine kinases might be important. Here we report that a new member of the Janus family of kinases (Jak-3) is coupled to the IL-2R in human peripheral blood T cells and natural killer cells.

Bestatin enhanced the antitumor effects of mitomycin C, 5-fluorouracil and cis-dichlorodiammineplatinum against a syngeneic solid tumor of colon adenocarcinoma 26 in BALB/c mice. The enhancement was dependent on administration schedule. Bestatin administration after treatment with the cytotoxic agents was more effective than that made before the treatment.

The effect of ubenimex on the release of interleukin 1 (IL-1) and interleukin 2 (IL-2) from immuno-competent cells was studied. Ubenimex enhanced release of IL-1 from mouse peritoneal macrophages at 1.0 and 100 micrograms/ml in vitro and the release at 1.0 microgram/ml was larger. When ubenimex was administered to mice IL-1-releasing activity of the peritoneal macrophages was enhanced 3 and 5 days after the administration but not enhanced 1 day after the administration. Ubenimex also enhanced IL-2 release from rat spleen cells at 0.1 and 10 micrograms/ml, when concanavalin A (Con A) was added in the IL-2-releasing system. The enhancement was still observed with mouse spleen cells, when serum was further added. Moreover, thymocyte-proliferating activity was attained in the broths which rat spleen cells were incubated with ubenimex from 0.1 to 10 micrograms/ml in the absence and presence of Con A.

The effect of ubenimex on the progression of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced stomach tumor in rats was studied. Tumor induction was performed by giving MNNG via drinking water for 34 weeks. Ubenimex was ip administered twice a week at 0.5 mg/kg for 84 weeks in one group and 49 weeks in another starting from the first and 36th weeks after initiation of MNNG administration, respectively. The stomachs were endoscopically examined 2 times. At the 64th week after initiation of MNNG administration tumorous lesions were observed with about 70% of the rats in both ubenimex administration groups. In the ubenimex non-administration group nearly 90% of the rats had the lesions. After completion of ubenimex administration almost all the rats had the lesions in the three groups but the sizes were much smaller with the two ubenimex administration groups. Almost all of these lesions were histopathologically identified as tumorous. The tumor volume per rat in the two ubenimex administration groups from the 1 and 36th weeks was 21.0 and 19.2% of the volume in the control group, respectively. Tumor number per rat was similar among the three groups. The natural killer activity of rats was also examined after completion of the above experiment. The activity markedly increased when ubenimex was administered from the 36th week after initiation of MNNG administration. When ubenimex was administered from the first week, the activity did not increase demonstratively. From all the results described above we conclude that ubenimex exerts an inhibitory action against the progression of MNNG-induced stomach tumor in rats. Contribution of the increase of natural killer activity to ubenimex antitumor action may be dependent on schedule of ubenimex administration.