Mirtazapine plus granisetron and dexamethasone for carboplatin-induced nausea and vomiting in patients with thoracic cancers: A prospective multicenter phase II trial.

BACKGROUND: Mirtazapine blocks 5-hydroxytryptamine type (5-HT)2A, 5-HT2C, 5-HT3 and histamine H1 receptors, similarly to olanzapine. This study aimed to investigate the efficacy and safety of mirtazapine plus granisetron and dexamethasone for carboplatin (CBDCA)-induced nausea and vomiting in patients with thoracic cancers. METHODS: We conducted a prospective, open-label, single-arm, multicenter, phase II trial in four institutions in Japan. Registered patients were moderately to highly emetogenic chemotherapy-naïve, and were scheduled to receive CBDCA at area under the curve (AUC) ≥ 4 mg/mL per minute. Patients received mirtazapine 15 mg/day orally at bedtime for four consecutive days, in combination with granisetron and dexamethasone. Primary endpoint was complete response (CR; no emesis and no use of rescue medication) rate during the delayed period (24-120 h). RESULTS: Between July 2022 and July 2023, 52 patients were enrolled, and 48 patients were evaluated. CR rates in the delayed (24-120 h), overall (0-120 h), and acute periods (0-24 h) were 83.3%, 83.3%, and 100%, respectively. No grade 3 or higher treatment-related adverse events were observed except for one patient who had grade 3 dry mouth as evaluated by Common Terminology Criteria for Adverse Events version 5.0. CONCLUSIONS: Prophylactic antiemetic therapy with mirtazapine plus granisetron and dexamethasone shows promising efficacy and an acceptable safety profile. This three-drug combination appears to be a reasonable treatment approach in patients with thoracic cancers receiving a CBDCA-based regimen at AUC ≥ 4 mg/mL per minute.

Modeling the effect of rainfall changes to predict population dynamics of the Asian tiger mosquito Aedes albopictus under future climate conditions.

The population dynamics of mosquitoes in temperate regions are not as well understood as those in tropical and subtropical regions, despite concerns that vector-borne diseases may be prevalent in future climates. Aedes albopictus, a vector mosquito in temperate regions, undergoes egg diapause while overwintering. To assess the prevalence of mosquito-borne diseases in the future, this study aimed to simulate and predict mosquito population dynamics under estimated future climatic conditions. In this study, we tailored the physiology-based climate-driven mosquito population (PCMP) model for temperate mosquitoes to incorporate egg diapauses for overwintering. We also investigated how the incorporation of the effect of rainfall on larval carrying capacity (into a model) changes the population dynamics of this species under future climate conditions. The PCMP model was constructed to simulate mosquito population dynamics, and the parameters of egg diapause and rainfall effects were estimated for each model to fit the observed data in Tokyo. We applied the global climate model data to the PCMP model and observed an increase in the mosquito population under future climate conditions. By applying the PCMP models (with or without the rainfall effect on the carrying capacity of the A. albopictus), our projections indicated that mosquito population dynamics in the future could experience changes in the patterns of their active season and population abundance. According to our results, the peak population number simulated using the highest CO2 emission scenario, while incorporating the rainfall effect on the carrying capacity, was approximately 1.35 times larger than that predicted using the model that did not consider the rainfall effect. This implies that the inclusion of rainfall effects on mosquito population dynamics has a major impact on the risk assessments of mosquito-borne diseases in the future.

Local atmospheric response to warm mesoscale ocean eddies in the Kuroshio-Oyashio Confluence region.

In the extratropical regions, surface winds enhance upward heat release from the ocean to atmosphere, resulting in cold surface ocean: surface ocean temperature is negatively correlated with upward heat flux. However, in the western boundary currents and eddy-rich regions, the warmer surface waters compared to surrounding waters enhance upward heat release-a positive correlation between upward heat release and surface ocean temperature, implying that the ocean drives the atmosphere. The atmospheric response to warm mesoscale ocean eddies with a horizontal extent of a few hundred kilometers remains unclear because of a lack of observations. By conducting regional atmospheric model experiments, we show that, in the Kuroshio-Oyashio Confluence region, wintertime warm eddies heat the marine atmospheric boundary layer (MABL), and accelerate westerly winds in the near-surface atmosphere via the vertical mixing effect, leading to wind convergence around the eastern edge of eddies. The warm-eddy-induced convergence forms local ascending motion where convective precipitation is enhanced, providing diabatic heating to the atmosphere above MABL. Our results indicate that warm eddies affect not only near-surface atmosphere but also free atmosphere, and possibly synoptic atmospheric variability. A detailed understanding of warm eddy-atmosphere interaction is necessary to improve in weather and climate projections.

Surgical intervention for vertebral metastases may benefit lung cancer patients no less than other patients: a retrospective study.

BACKGROUND: Spinal metastasis is considered to have a worse prognosis in lung cancer than in other cancers, but recent clinical studies report improved overall survival of lung cancer. We compared the postoperative prognoses of vertebral metastatic tumors from lung with other types of cancer. METHODS: From 2011 to 2015, 31 Japanese patients (mean age 73 years, range 55-88 years; 19 males, 12 females) underwent surgery for spinal metastasis at our center. We observed patients retrospectively in March 2016, dividing them into groups by cancer type: lung (LK group, n = 10); prostate, breast, or thyroid (PB group, n = 12); and other (OT group, n = 9). We compared survival and revised Tokuhashi score, which provides a basis for choosing a treatment course. Neurologic status was graded before and after surgery using the Frankel system. RESULTS: Mean follow-up was 16.5 months (range 1-62 months). Only seven of 31 patients (22.6%) were alive at final follow-up. Frankel grade significantly improved postoperatively only in the LK (P = 0.01) and PB (P = 0.048) groups. Revised Tokuhashi score differed across groups (P < 0.0001), and was significantly lower in the LK group than in the PB group (P = 0.00) and OT group (P = 0.02). Postoperative survival was significantly shorter in the LK group than in the PB group (P = 0.01) but did not differ between the LK and OT groups. CONCLUSIONS: The revised Tokuhashi score may underestimate the survival of lung cancer patients, who may derive the same benefit from surgical intervention as those with vertebral metastasis from other cancer types.

Spatial niche facilitates clonal reproduction in seed plants under temporal disturbance.

The evolutionary origins and advantages of clonal reproduction relative to sexual reproduction have been discussed for several taxonomic groups. In particular, organisms with a sessile lifestyle are often exposed to spatial and temporal environmental fluctuations. Thus, clonal propagation may be advantageous in such fluctuating environments, for sessile species that can reproduce both sexually and clonally. Here we introduce the concept of niche to a lattice space that changes spatially and temporally, by incorporating the compatibility between the characteristics of a sessile clonal plant with its habitat into a spatially explicit individual-based model. We evaluate the impact of spatially and temporally heterogeneous environments on the evolution of reproductive strategies: the optimal balance between seed and clonal reproduction of a clonal plant. The spatial niche case with local habitats led to avoidance of specialization in reproductive strategy, whereas stable environments or intensive environmental change tended to result in specialization in either clonal or seed reproduction under neutral conditions. Furthermore, an increase in spatial niches made clonal reproduction advantageous, as a consequence of competition among several genets under disturbed conditions, because a ramet reached a favorable habitat through a rare long-distance dispersal event via seed production. Thus, the existence of spatial niches could explain the advantages of clonal propagation.

Evolution of symbiosis with resource allocation from fecundity to survival.

Symbiosis is one of the most fundamental relationships between or among organisms and includes parasitism (which has negative effects on the fitness of the interacting partner), commensalism (no effect), and mutualism (positive effects). The effects of these interactions are usually assumed to influence a single component of a species' fitness, either survival or fecundity, even though in reality the interaction can simultaneously affect both of these components. I used a dual lattice model to investigate the process of evolution of mutualistic symbiosis in the presence of interactive effects on both survival and fecundity. I demonstrate that a positive effect on survival and a negative effect on fecundity are key to the establishment of mutualism. Furthermore, both the parasitic and the mutualistic behaviour must carry large costs for mutualism to evolve. This helps develop a new understanding of symbiosis as a function of resource allocation, in which resources are shifted from fecundity to survival. The simultaneous establishment of mutualism from parasitism never occurs in two species, but can do so in one of the species as long as the partner still behaves parasitically. This suggests that one of the altruistic behaviours in a mutualistic unit consisting of two species must originate as a parasitic behaviour.

Functional diversity of microbial decomposers facilitates plant coexistence in a plant-microbe-soil feedback model.

Theory and empirical evidence suggest that plant-soil feedback (PSF) determines the structure of a plant community and nutrient cycling in terrestrial ecosystems. The plant community alters the nutrient pool size in soil by affecting litter decomposition processes, which in turn shapes the plant community, forming a PSF system. However, the role of microbial decomposers in PSF function is often overlooked, and it remains unclear whether decomposers reinforce or weaken litter-mediated plant control over nutrient cycling. Here, we present a theoretical model incorporating the functional diversity of both plants and microbial decomposers. Two fundamental microbial processes are included that control nutrient mineralization from plant litter: (i) assimilation of mineralized nutrient into the microbial biomass (microbial immobilization), and (ii) release of the microbial nutrients into the inorganic nutrient pool (net mineralization). With this model, we show that microbial diversity may act as a buffer that weakens plant control over the soil nutrient pool, reversing the sign of PSF from positive to negative and facilitating plant coexistence. This is explained by the decoupling of litter decomposability and nutrient pool size arising from a flexible change in the microbial community composition and decomposition processes in response to variations in plant litter decomposability. Our results suggest that the microbial community plays a central role in PSF function and the plant community structure. Furthermore, the results strongly imply that the plant-centered view of nutrient cycling should be changed to a plant-microbe-soil feedback system, by incorporating the community ecology of microbial decomposers and their functional diversity.

Endosymbiosis as a compact ecosystem with material cycling: parasitism or mutualism?

To discover the evolutionary logic of intracellular endosymbiosis, we investigated a theoretical model (simultaneous ordinary differential equations) of a material-cycling system inside a host cell. In the model, we introduced a recently developed cell biology concept called "autophagy", which is a decomposing-recycle process of self-compiled materials found universally among eukaryote cells. Our model is based on traditional simultaneous ODE for natural ecosystems that involve producing, grazing, and decomposing processes in material cycling. In the basic intracellular metabolic system, several enzymes regulate metabolism by synthesizing and converting metabolites into biomolecules that are precursors for enzymes involved in the producing process. Symbionts are involved in grazing processes and autophagosomes that degrade materials are involved in decomposing recycles. We compared and analyzed the local stability of ODE systems in three cases: (1) the independent, free-living cell (the basal state of a cell), (2) the case where symbionts invade and exploit macrobiomaterials as parasites inside a host cell, and (3) the combination where symbionts assist the host's metabolism. We conclude that: (i) as consumers, symbionts are required to have a growth rate that is higher than the rate of autophagosome decomposition, (ii) the host cell with a biomass larger than the threshold size would realize the mutualistic relationship with its symbiont, and (iii) this partnership accelerates the biomaterial turnover flow on the basis of biomaterials.

Antitussive effects of the H1-receptor antagonist epinastine in patients with atopic cough (eosinophilic bronchitis).

Chronic cough is the only symptom of eosinophilic bronchitis (EB). There is considerable overlap between EB and atopic cough. To investigate the antitussive effects of a histamine H1-recetor antagonist, epinastine hydrochloride (epinastine, CAS 80012-43-7, Alesion; 20 mg/day, once daily), cough scores, pulmonary function, capsaicin cough threshold, and bronchial hyperresonsiveness (BHR) to methacholine (MCh) were evaluated before and after a 4-week treatment with epinastine in patients with EB. In the epinastine group, the cough scores were decreased significantly (18.3 +/- 6.1 in week 1, 17.4 +/- 6.7 in week 2, 15.1 +/- 6.2 in week 3, 14.0 +/- 4.8 in week 4) in comparison with the value of 35.3 +/- 8.7 in week -2). The cough threshold for capsaicin improved from 1.70 +/- 3.04 micromol/l to 12.7 +/- 17.6 micromol/l in the epinastine group (p < 0.05; baseline vs. week 4) The bronchial hyperresponsiveness to MCh (Dmin) did not change significantly either in the epinastine or the placebo groups. The morning and evening peak expiratory flow rate (PEFR, L/min) did not change from the baseline period in either the epinastine or the placebo groups. These results suggested that epinastine may be useful for treating patients with EB and that histamine H1-receptor is related to the pathophysiology of coughing in EB.

Poorly controlled ulcerative colitis treated by colectomy during remission induced by extracorporeal leukocyte removal therapy.

Both monocyte-granulocytapheresis (M-GCAP) and leukocytapheresis (LCAP) are categorized as extracorporeal leukocyte removal therapies (ECCTs). These therapies have been recognized as efficient adjuncts for patients of steroid-resistant ulcerative colitis (UC). This study aimed to consider the adaptation and the limitation of these new therapies from the clinical standpoint based on a case of UC showing strong resistance to high-dose continuous steroid injection therapy. The patient successfully underwent a scheduled colectomy while maintaining remission after applying M-GCAP and LCAP independently. Surgical therapy was chosen because of a deep ulcer in the patient's sigmoid colon, which was assumed to constitute a future risk for perforation. This case suggests that combining ECCT with steroid therapy can maintain such poorly controlled and high-risk UC patients safely for the scheduled colectomy while improving the prognosis by reducing the dosage of steroid efficiently prior to operation.

Extracorporeal monocyte granulocytapheresis was effective for a patient of erythema nodosum concomitant with ulcerative colitis.

We report an erythema nodosum (EN) patient whose condition became apparent during the clinical course of ulcerative colitis (UC). The patient relapsed frequently in spite of taking a high dose adrenocortical steroid during his morbidity period of UC. Monocyte-granulocytapheresis (M-GCAP) was combined with 5-aminosalicylic acid 2250 mg/day peroral and once a day of steroid enema. Monocyte-granulocytapheresis was performed once a week for 5 weeks, and succeeded in inducing clinical remission for both UC and EN. The immunological and clinical connections between UC and EN have never been fully elucidated. In this case, because the symptoms of UC and EN revealed parallel improvement after his inflammatory reaction had been brought under control by combining M-GCAP therapy, we hypothesize that the onset of EN appeared as a result of the patient's long-term, treatment-resistant immuno-disturbance, which first appeared as symptoms of UC. Immunomodulative effects induced by M-GCAP might help to control other chronic non-specific inflammations not concerned with targeted organ(s).

Polymorphisms of the TNF gene and the TNF receptor superfamily member 1B gene are associated with susceptibility to ulcerative colitis and Crohn's disease, respectively.

The importance of tumor necrosis factor (TNF)-alpha and the TNF receptor gene polymorphisms in the etipathogenesis of inflammatory bowel disease (IBD) has not been elucidated. DNA from peripheral blood samples was obtained from 124 patients with Crohn's disease (CD), 106 patients with ulcerative colitis (UC), and 111 unrelated healthy controls. We examined two single nucleotide polymorphisms (SNPs) of the TNF-alpha gene, TNF (-308 G/A and -238 G/A), an SNP of the TNF receptor superfamily member 1A gene, TNFRSF1A(also known as TNFR1), at codon 12 in exon 1 (CCA/CCG), and two SNPs of the 1B gene, TNFRSF1B (also known as TNFR2), (1466 A/G and 1493 C/T). There was a difference in the carrier frequency for haplotype AG (-308 A, -238 G) between UC patients and the controls (OR=4.76, 95% CI=1.53-14.74, P<0.01). We found a significant difference in carrier frequency for haplotype AT (1466 A, 1493 T) of the TNFRSF1B gene between CD patients and the controls (OR=2.13, 95% CI=1.08-4.21, P<0.05). The significance proved to be greater in CD patients with both internal and external fistula (OR=4.8, 95% CI=1.73-13.33, P<0.01), and in those who were poor responders ( n=22) to our treatments, which consisted of nutritional therapy, medical therapy and surgical therapy (OR=9.24, 95% CI=3.37-25.36, P<0.001). This study suggests that one of the genes responsible for UC may be the TNF gene, or an adjacent gene, and that TNFRSF1B gene polymorphisms contribute greatly to the increased onset risk of CD and to the disease behavior.

A case report: first case of filtration leukocytapheresis for a patient of aortitis syndrome associated with ulcerative colitis.

An 18-year-old woman was treated with leukocytapheresis (LCAP) for her combined ulcerative colitis (UC) and aortitis syndrome (AS). Because a close relationship between these two diseases has been suspected based on their etiological and/or pathological findings, we had hypothesized that LCAP, which has satisfactory effects on inflammatory bowel disease such as UC and Crohn's disease might be effective for both her UC and her AS. After informed consent, LCAP therapy was performed once a week for a total of 7 times. Endoscopic remission of the UC was observed. Even though there were no significant improvements in her subjective symptoms of AS such as side-neck pain and dizziness, objective evidence of improvement was obtained when the patient's condition was compared before and after LCAP by angiography, angio-magnetic resonance imaging, and the plethysmogram of her fingertips. These results suggest that LCAP may be valuable as a new adjunct therapy for AS.

IL18 polymorphism is associated with an increased risk of Crohn's disease.

BACKGROUND: The etiology of inflammatory bowel disease, which includes ulcerative colitis and Crohn's disease, has not yet been made clear. However, inflammatory bowel disease is recognized as a multifactorial disease, and innate genetic factors might contribute to the pathogenesis. Cytokine genes are thought to be important in inflammatory bowel disease. Recently, interleukin 18, cloned as a novel proinflammatory cytokine, has been implicated in inflammatory bowel disease, especially Crohn's disease. METHODS: To identify germline mutations in patients with inflammatory bowel disease, the entire coding region of IL18 was examined using a DNA sequencing procedure. RESULTS: No functional mutations were found, but a novel single nucleotide polymorphism (SNP) was identified as TCA/TCC at codon 35. In patients with Crohn's disease, the frequency of TCC allele carriers was significantly higher than in healthy controls (chi2 = 9.35, P = 0.002229, OR = 2.58, 95% CI = 1.39-4.80). Also, the magnitude of the association was more remarkable in females (chi2 = 16.36, P = 0.000052, OR = 8.17, 95% CI = 2.73-24.41). The TCC allele at codon 35 of IL18 may increase the risk for Crohn's disease, especially in females. CONCLUSIONS: IL18 is probably one of several genes that determine susceptibility to Crohn's disease.