CAF-associated genes putatively representing distinct prognosis by in silico landscape of stromal components of colon cancer.

Comprehensive understanding prognostic relevance of distinct tumor microenvironment (TME) remained elusive in colon cancer. In this study, we performed in silico analysis of the stromal components of primary colon cancer, with a focus on the markers of cancer-associated fibroblasts (CAF) and tumor-associated endothelia (TAE), as well as immunological infiltrates like tumor-associated myeloid cells (TAMC) and cytotoxic T lymphocytes (CTL). The relevant CAF-associated genes (CAFG)(representing R index = 0.9 or beyond with SPARC) were selected based on stroma specificity (cancer stroma/epithelia, cS/E = 10 or beyond) and expression amounts, which were largely exhibited negative prognostic impacts. CAFG were partially shared with TAE-associated genes (TAEG)(PLAT, ANXA1, and PTRF) and TAMC-associated genes (TAMCG)(NNMT), but not with CTL-associated genes (CTLG). Intriguingly, CAFG were prognostically subclassified in order of fibrosis (representing COL5A2, COL5A1, and COL12A1) followed by exclusive TAEG and TAMCG. Prognosis was independently stratified by CD8A, a CTL marker, in the context of low expression of the strongest negative prognostic CAFG, COL8A1. CTLG were comprehensively identified as IFNG, B2M, and TLR4, in the group of low S/E, representing good prognosis. Our current in silico analysis of the micro-dissected stromal gene signatures with prognostic relevance clarified comprehensive understanding of clinical features of the TME and provides deep insights of the landscape.

Physiologically based pharmacokinetic modeling to predict the clinical effect of azole antifungal agents as CYP3A inhibitors on azelnidipine pharmacokinetics.

In this study, a physiologically based pharmacokinetic (PBPK) model of the cytochrome P450 3A (CYP3A) substrate azelnidipine was developed using in vitro and clinical data to predict the effects of azole antifungals on azelnidipine pharmacokinetics. Modeling and simulations were conducted using the Simcyp™ PBPK simulator. The azelnidipine model consisted of a full PBPK model and a first-order absorption model. CYP3A was assumed as the only azelnidipine elimination route, and CYP3A clearance was optimized using the pharmacokinetic profile of single-dose 5-mg azelnidipine in healthy participants. The model reproduced the results of a clinical drug-drug interaction study and met validation criteria. PBPK model simulations using azole antifungals (itraconazole, voriconazole, posaconazole, fluconazole, fosfluconazole) and azelnidipine or midazolam (CYP3A index substrate) were performed. Increases in the simulated area under the plasma concentration-time curve from time zero extrapolated to infinity with inhibitors were comparable between azelnidipine (range, 2.11-6.47) and midazolam (range, 2.26-9.22), demonstrating that azelnidipine is a sensitive CYP3A substrate. Increased azelnidipine plasma concentrations are expected when co-administered with azole antifungals, potentially affecting azelnidipine safety. These findings support the avoidance of azole antifungals in patients taking azelnidipine and demonstrate the utility of PBPK modeling to inform appropriate drug use.

Physiologically Based Pharmacokinetic Absorption Model for Pexidartinib to Evaluate the Impact of Meal Contents and Intake Timing on Drug Exposure.

Pexidartinib is a systemic treatment for patients with tenosynovial giant cell tumor not amenable to surgery. Oral absorption of pexidartinib is affected by food; administration with a high-fat meal (HFM) or low-fat meal (LFM) increases absorption by approximately 100% and approximately 60%, respectively, compared with the fasted state. Pexidartinib is currently dosed 250 mg orally twice daily with an LFM (approximately 11-14 g of total fat). We developed a physiologically based pharmacokinetic model to determine the impact on drug exposure of dose timing with respect to meals, meal type, and caloric content. A 15%-16% increase in plasma exposure was predicted when consuming an HFM 1 hour after dosing with an LFM, but almost no effect on pharmacokinetics was predicted when an HFM was consumed 3 hours or more before or after pexidartinib dosing with an LFM. Exposure was not significantly affected when pexidartinib was taken with a 500-kcal LFM over the range of fat (approximately 11-14 g of total fat; 20%-25% calories from fat) for an LFM. These findings on timing of pexidartinib dose with respect to meals should be considered by patients and physicians to reduce the potential for side effects.

Low skeletal muscle radiodensity is a risk factor for adjuvant chemotherapy discontinuation in colorectal cancer.

BACKGROUND: Previously, we reported SMR (skeletal muscle radiodensity) as a potential prognostic marker for colorectal cancer. However, there have been limited studies on the association between SMR and the continuation of adjuvant chemotherapy in colorectal cancer. METHODS: In this retrospective study, 143 colorectal cancer patients underwent curative surgery and adjuvant chemotherapy using the CAPOX regimen. Patients' SMRs were measured from preoperative CT images and divided into low (bottom quarter) and high (top three quarters) SMR groups. We compared chemotherapy cycles, capecitabine and oxaliplatin doses, and adverse effects in each group. RESULTS: The low SMR group had significantly fewer patients completing adjuvant chemotherapy compared to the high SMR group (44% vs. 68%, P < 0.01). Capecitabine and oxaliplatin doses were also lower in the low SMR group. Incidences of Grade 2 or Grade 3 adverse effects did not differ between groups, but treatment discontinuation due to adverse effects was significantly higher in the low SMR group. Logistic regression analysis revealed Stage III disease (odds ratio 18.09, 95% CI 1.41-231.55) and low SMR (odds ratio 3.26, 95% CI 1.11-9.56) as factors associated with unsuccessful treatment completion. Additionally, a higher proportion of low SMR patients received fewer than 2 cycles of chemotherapy (50% vs. 12%). CONCLUSION: The low SMR group showed higher treatment incompletion rates and received lower drug doses during adjuvant chemotherapy. Low SMR independently contributed to treatment non-completion in colorectal cancer patients.

Protective human antibodies against a conserved epitope in pre- and postfusion influenza hemagglutinin.

Phylogenetically and antigenically distinct influenza A and B viruses (IAV and IBV) circulate in human populations, causing widespread morbidity. Antibodies (Abs) that bind epitopes conserved in both IAV and IBV hemagglutinins (HAs) could protect against disease by diverse virus subtypes. Only one reported HA Ab, isolated from a combinatorial display library, protects against both IAV and IBV. Thus, there has been so far no information on the likelihood of finding naturally occurring human Abs that bind HAs of diverse IAV subtypes and IBV lineages. We have now recovered from several unrelated human donors five clonal Abs that bind a conserved epitope preferentially exposed in the postfusion conformation of IAV and IVB HA2. These Abs lack neutralizing activity in vitro but in mice provide strong, IgG subtype-dependent protection against lethal IAV and IBV infections. Strategies to elicit similar Abs routinely might contribute to more effective influenza vaccines.

A new class of antibodies that overcomes a steric barrier to cross-group neutralization of influenza viruses.

Antibody titers that inhibit the influenza virus hemagglutinin (HA) from engaging its receptor are the accepted correlate of protection from infection. Many potent antibodies with broad, intra-subtype specificity bind HA at the receptor binding site (RBS). One barrier to broad H1-H3 cross-subtype neutralization is an insertion (133a) between positions 133 and 134 on the rim of the H1 HA RBS. We describe here a class of antibodies that overcomes this barrier. These genetically unrestricted antibodies are abundant in the human B cell memory compartment. Analysis of the affinities of selected members of this class for historical H1 and H3 isolates suggest that they were elicited by H3 exposure and broadened or diverted by later exposure(s) to H1 HA. RBS mutations in egg-adapted vaccine strains cause the new H1 specificity of these antibodies to depend on the egg adaptation. The results suggest that suitable immunogens might elicit 133a-independent, H1-H3 cross neutralization by RBS-directed antibodies.

Hydrogen sulfide and polysulfides induce GABA/glutamate/D-serine release, facilitate hippocampal LTP, and regulate behavioral hyperactivity.

Hydrogen sulfide (H2S) and polysulfides (H2Sn, n ≥ 2) are signaling molecules produced by 3-mercaptopyruvate sulfurtransferase (3MST) that play various physiological roles, including the induction of hippocampal long-term potentiation (LTP), a synaptic model of memory formation, by enhancing N-methyl-D-aspartate (NMDA) receptor activity. However, the presynaptic action of H2S/H2Sn on neurotransmitter release, regulation of LTP induction, and animal behavior are poorly understood. Here, we showed that H2S/H2S2 applied to the rat hippocampus by in vivo microdialysis induces the release of GABA, glutamate, and D-serine, a co-agonist of NMDA receptors. Animals with genetically knocked-out 3MST and the target of H2S2, transient receptor potential ankyrin 1 (TRPA1) channels, revealed that H2S/H2S2, 3MST, and TRPA1 activation play a critical role in LTP induction, and the lack of 3MST causes behavioral hypersensitivity to NMDA receptor antagonism, as in schizophrenia. H2S/H2Sn, 3MST, and TRPA1 channels have therapeutic potential for psychiatric diseases and cognitive deficits.

Less demand on stem cell marker-positive cancer cells may characterize metastasis of colon cancer.

BACKGROUND: CD44 and CD133 are stem cell markers in colorectal cancer (CRC). CD44 has distinctive isoforms with different oncological properties like total CD44 (CD44T) and variant CD44 (CD44V). Clinical significance of such markers remains elusive. METHODS: Sixty colon cancer were examined for CD44T/CD44V and CD133 at mRNA level in a quantitative PCR, and clarified for their association with clinicopathological factors. RESULTS: (1) Both CD44T and CD44V showed higher expression in primary colon tumors than in non-cancerous mucosas (p<0.0001), while CD133 was expressed even in non-cancerous mucosa and rather decreased in the tumors (p = 0.048). (2) CD44V expression was significantly associated with CD44T expression (R = 0.62, p<0.0001), while they were not correlated to CD133 at all in the primary tumors. (3) CD44V/CD44T expressions were significantly higher in right colon cancer than in left colon cancer (p = 0.035/p = 0.012, respectively), while CD133 expression were not (p = 0.20). (4) In primary tumors, unexpectedly, CD44V/CD44T/CD133 mRNA expressions were not correlated with aggressive phenotypes, but CD44V/CD44T rather significantly with less aggressive lymph node metastasis/distant metastasis (p = 0.040/p = 0.039, respectively). Moreover, both CD44V and CD133 expressions were significantly decreased in liver metastasis as compared to primary tumors (p = 0.0005 and p = 0.0006, respectively). CONCLUSION: Our transcript expression analysis of cancer stem cell markers did not conclude that their expression could represent aggressive phenotypes of primary and metastatic tumors, and rather represented less demand on stem cell marker-positive cancer cells.

Short-term outcomes of robot-assisted versus conventional laparoscopic surgery for mid and low rectal cancer after neoadjuvant chemoradiotherapy: a propensity score-matched analysis.

The benefits of robot-assisted laparoscopic surgery (RALS) for rectal cancer remain controversial. Only a few studies have evaluated the safety and feasibility of RALS following neoadjuvant chemoradiotherapy (NCRT). This study aimed to compare the short-term outcomes of RALS versus conventional laparoscopic surgery (CLS) after NCRT for rectal cancer. Propensity score matching of 111 consecutive patients who underwent RALS or CLS after NCRT for rectal adenocarcinoma between February 2014 and February 2022 was performed. Among them, 60 matched patients were enrolled and their short-term outcomes were compared. Although operative time, conversion rate to open laparotomy and blood loss were comparable, the incidence of postoperative complications, including anastomotic leakage, was significantly lower, urinary retention tended to be lower, and the days to soft diet intake and postoperative hospital stay were significantly shorter in the RALS than the CLS group. No postoperative mortality was observed in either group, and there were no significant differences in terms of resection margins and number of lymph nodes dissected. RALS after NCRT for rectal cancer is safe and technically feasible, and has acceptable short-term outcomes. Further studies are required for validation of the long-term oncological outcomes.

Quantitative Evaluation of the Contribution of Each Aldo-Keto Reductase and Short-Chain Dehydrogenase/Reductase Isoform to Reduction Reactions of Compounds Containing a Ketone Group in the Human Liver.

Enzymes of the aldo-keto reductase (AKR) and short-chain dehydrogenase/reductase superfamilies are involved in the reduction of compounds containing a ketone group. In most cases, multiple isoforms appear to be involved in the reduction of a compound, and the enzyme(s) that are responsible for the reaction in the human liver have not been elucidated. The purpose of this study was to quantitatively evaluate the contribution of each isoform to reduction reactions in the human liver. Recombinant cytosolic isoforms were constructed, i.e., AKR1C1, AKR1C2, AKR1C3, AKR1C4, and carbonyl reductase 1 (CBR1), and a microsomal isoform, 11ß-hydroxysteroid dehydrogenase type 1 (HSD11B1), and their contributions to the reduction of 10 compounds were examined by extrapolating the relative expression of each reductase protein in human liver preparations to recombinant systems quantified by liquid chromatography-mass spectrometry. The reductase activities for acetohexamide, doxorubicin, haloperidol, loxoprofen, naloxone, oxcarbazepine, and pentoxifylline were predominantly catalyzed by cytosolic isoforms, and the sum of the contributions of individual cytosolic reductases was almost 100%. Interestingly, AKR1C3 showed the highest contribution to acetohexamide and loxoprofen reduction, although previous studies have revealed that CBR1 mainly metabolizes them. The reductase activities of bupropion, ketoprofen, and tolperisone were catalyzed by microsomal isoform(s), and the contributions of HSD11B1 were calculated to be 41%, 32%, and 104%, respectively. To our knowledge, this is the first study to quantitatively evaluate the contribution of each reductase to the reduction of drugs in the human liver. SIGNIFICANCE STATEMENT: To our knowledge, this is the first study to determine the contribution of aldo-keto reductase (AKR)-1C1, AKR1C2, AKR1C3, AKR1C4, carbonyl reductase 1, and 11ß-hydroxysteroid dehydrogenase type 1 to drug reductions in the human liver by utilizing the relative expression factor approach. This study found that AKR1C3 contributes to the reduction of compounds at higher-than-expected rates.

A broad antibody class engages the influenza virus hemagglutinin head at its stem interface.

Influenza infection and vaccination impart strain-specific immunity that fails to protect against both seasonal antigenic variants and the next pandemic. However, antibodies directed to conserved sites can confer broad protection. We identify and characterize a class of human antibodies that engage a previously undescribed, conserved, epitope on the influenza hemagglutinin protein (HA). Prototype antibody S8V1-157 binds at the normally occluded interface between the HA head and stem. Antibodies to this HA head-stem interface epitope are non-neutralizing in vitro but protect against lethal infection in mice. Their breadth of binding extends across most influenza A serotypes and seasonal human variants. Antibodies to the head-stem interface epitope are present at low frequency in the memory B cell populations of multiple donors. The immunogenicity of the epitope warrants its consideration for inclusion in improved or "universal" influenza vaccines.

Altered distribution of resting periods of daily locomotor activity in patients with delayed sleep phase disorder.

Delayed sleep phase disorder (DSPD) and mood disorders have a close relationship. However, the shared mechanisms by DSPD and mood disorders have not been well-elucidated. We previously found that micro-fluctuations in human behaviors are organized by robust statistical laws (behavioral organization), where the cumulative distributions of resting and active period durations take a power-law distribution form and a stretched exponential functional form, respectively. Further, we found that the scaling exponents of resting period distributions significantly decreased in major depressive disorder (MDD). In this study, we hypothesized that DSPD had similar characteristics of the altered behavioral organization to that of MDD. Locomotor activity data were acquired for more than 1 week from 17 patients with DSPD and 17 age- and gender-matched healthy participants using actigraphy. We analyzed the cumulative distributions of resting and active period durations in locomotor activity data and subsequently derived fitting parameters of those distributions. Similar to patients with MDD, we found that resting period distributions took a power-law form over the range of 2-100 min, with significantly lower values of scaling exponents γ in patients with DSPD compared with healthy participants. The shared alteration in γ suggests the existence of similar pathophysiology between DSPD and MDD.

Infant Antibody Repertoires during the First Two Years of Influenza Vaccination.

The first encounter with influenza virus biases later immune responses. This "immune imprinting," formerly from infection within a few years of birth, is in the United States now largely from immunization with a quadrivalent, split vaccine (IIV4 [quadrivalent inactivated influenza vaccine]). In a pilot study of IIV4 imprinting, we used single-cell cultures, next-generation sequencing, and plasma antibody proteomics to characterize the primary antibody responses to influenza in two infants during their first 2 years of seasonal influenza vaccination. One infant, who received only a single vaccination in year 1, contracted an influenza B virus (IBV) infection between the 2 years, allowing us to compare imprinting by infection and vaccination. That infant had a shift in hemagglutinin (HA)-reactive B cell specificity from largely influenza A virus (IAV) specific in year 1 to IBV specific in year 2, both before and after the year 2 vaccination. HA-reactive B cells from the other infant maintained a more evenly distributed specificity. In year 2, class-switched HA-specific B cell IGHV somatic hypermutation (SHM) levels reached the average levels seen in adults. The HA-reactive plasma antibody repertoires of both infants comprised a relatively small number of antibody clonotypes, with one or two very abundant clonotypes. Thus, after the year 2 boost, both infants had overall B cell profiles that resembled those of adult controls. IMPORTANCE Influenza virus is a moving target for the immune system. Variants emerge that escape protection from antibodies elicited by a previously circulating variant ("antigenic drift"). The immune system usually responds to a drifted influenza virus by mutating existing antibodies rather than by producing entirely new ones. Thus, immune memory of the earliest influenza virus exposure has a major influence on later responses to infection or vaccination ("immune imprinting"). In the many studies of influenza immunity in adult subjects, imprinting has been from an early infection, since only in the past 2 decades have infants received influenza immunizations. The work reported in this paper is a pilot study of imprinting by the flu vaccine in two infants, who received the vaccine before experiencing an influenza virus infection. The results suggest that a quadrivalent (four-subtype) vaccine may provide an immune imprint less dominated by one subtype than does a monovalent infection.

Bowel Perforation in a Patient with Hepatocellular Carcinoma during Lenvatinib Treatment.

We present a case of severe bowel perforation during lenvatinib treatment for advanced hepatocellular carcinoma. Although the Hartmann's procedure was performed, the patient died 48 h after the operation. The histopathological findings suggested that lenvatinib was involved in the etiology of bowel perforation in this case.

Short- and long-term outcomes of robotic-assisted laparoscopic surgery for rectal cancer: A single-center retrospective cohort study.

INTRODUCTION: Whether rectal cancer surgery by robotic-assisted laparoscopic surgery provides beneficial advantages remains controversial. Although favorable outcomes in terms of the safety and technical feasibility of robotic-assisted laparoscopic surgery have been demonstrated for rectal cancer, long-term oncological outcomes for robotic-assisted laparoscopic surgery have only been examined in a few studies. This retrospective study of subjects who underwent robotic-assisted laparoscopic surgery evaluated short- and long-term outcomes of consecutive rectal cancer patients. METHODS: Between November 2016 and January 2020, we analyzed the records of 62 consecutive patients who underwent robotic-assisted laparoscopic surgery for rectal adenocarcinoma without distant metastasis to evaluate short- and long-term outcomes. RESULTS: Tumors were located in the lower or mid-rectum (88.7%) in most patients. The median operative time was 357 min. No patient received transfusions, and the median blood loss was 10.5 ml. Open laparotomy was not required in any patient. A Clavien-Dindo classification of all grades was observed in 12 patients (19.4%). Positive radial margin was not observed in any patient. Duration of median follow-up was 40.5 mo, while 3-y overall survival and 3-y relapse-free survival rates were 96.8% and 85.0%, respectively. The local recurrence rate was 3.4%. CONCLUSION: Favorable short- and long-term outcomes demonstrated robotic-assisted laparoscopic surgery was safe and technically feasible for rectal cancer.

Species differences between rats and primates (humans and monkeys) in complex cleavage pathways of DS-8500a characterized by 14C-ADME studies in humans and monkeys after administration of two radiolabeled compounds and in vitro studies.

Our previous study in rats demonstrated that the metabolic pathways of DS-8500a, a novel GPR119 agonist, include cleavage pathways: reductive cleavage of the oxadiazole ring in the liver and hydrolysis of the amide side chain. In the present study, in vivo metabolic profiling in humans and monkeys after the oral administration of two 14C-labeled compounds was performed to investigate species differences of the cleavage pathways. In monkeys, the oxadiazole ring-cleaved metabolites were mainly detected in feces, but not observed in bile, unlike in rats, suggesting that the reductive ring-opening metabolism occurs in the gastrointestinal tract. In vitro incubation with enterobacterial culture media demonstrated that the reductive cleavage of the oxadiazole ring in humans and monkeys was considerably faster than that in rats. The other cleavage metabolite (M20), produced via hydrolysis of the amide side chain, was detected as the major plasma metabolite in humans and monkeys, and its subsequent metabolite (M21) was excreted in feces, whereas M21 was not a major component in rats, indicating a notable species difference in the amide hydrolysis. In conclusion, this study comprehensively revealed the pronounced species difference of the cleavage pathways: reductive ring-opening by intestinal microflora and liver, and amide hydrolysis.

Comparison of short-term outcomes of robotic-assisted and conventional laparoscopic surgery for rectal cancer: A propensity score-matched analysis.

INTRODUCTION: The advantages of robotic-assisted laparoscopic surgery (RALS) for rectal cancer remain controversial. This study clarified and compared the short-term outcomes of RALS for rectal cancer with those of conventional laparoscopic surgery (CLS). METHODS: The records of 303 consecutive patients who underwent RALS or CLS for rectal adenocarcinoma between November 2016 and November 2021 were analyzed using propensity score-matched analysis. After matching, 188 patients were enrolled in our study to compare short-term outcomes, such as operative results, postoperative complications, and pathological findings, in each group. RESULTS: After matching, baseline characteristics were comparable between groups. Although operative time in the RALS group was significantly longer than in the CLS group (p < 0.0001), the conversion rate to open laparotomy and the postoperative complication rate in the RALS group were significantly lower than in the CLS group (p = 0.0240 and p = 0.0109, respectively). Blood loss was comparable between groups. In the RALS group, postoperative hospital stay and days to soft diet were significantly shorter than those in the CLS group (p = 0.0464 and p < 0.0001, respectively). No postoperative mortality was observed in either group and significant differences were observed in resection margins and number of lymph nodes harvested. CONCLUSION: Robotic-assisted laparoscopic surgery for rectal cancer was safe, technically feasible, and had acceptable short-term outcomes. Further studies are required to validate long-term oncological outcomes.

Evaluation of protein production in rice seedlings under dark conditions.

Although plants have several advantages for foreign protein production, cultivation of transgenic plants in artificial plant growth facilities involves the use of a great amount of electricity for lightning and air conditioning, reducing cost-effectiveness. Protein production in plants grown in darkness can overcome this problem, but the amount of protein produced in the dark is unknown. In this study, the total amount of soluble protein produced in rice seedlings germinated and grown in light or darkness were examined at several time points after germination and under different temperature, nutritional, and seedling density conditions. Our results indicate that rice seedlings grown in darkness produce a comparable amount of total soluble protein to those grown in light. Furthermore, we found that the best conditions for protein production in dark-grown rice seedlings are large seeds germinated and grown for 10-12 days at 28 °C supplemented with Murashige and Skoog medium and 30 g/l sucrose in dense planting. Therefore, our results suggest that foreign proteins can be produced in rice seedlings in the dark, with a reduced electricity use and an increase in cost-effectiveness.

DS-7300a, a DNA Topoisomerase I Inhibitor, DXd-Based Antibody-Drug Conjugate Targeting B7-H3, Exerts Potent Antitumor Activities in Preclinical Models.

B7-H3 is overexpressed in various solid tumors and has been considered as an attractive target for cancer therapy. Here, we report the development of DS-7300a, a novel B7-H3-targeting antibody-drug conjugate with a potent DNA topoisomerase I inhibitor, and its in vitro profile, pharmacokinetic profiles, safety profiles, and in vivo antitumor activities in nonclinical species. The target specificity and species cross-reactivity of DS-7300a were assessed. Its pharmacologic activities were evaluated in several human cancer cell lines in vitro and xenograft mouse models, including patient-derived xenograft (PDX) mouse models in vivo. Pharmacokinetics was investigated in cynomolgus monkeys. Safety profiles in rats and cynomolgus monkeys were also assessed. DS-7300a specifically bound to B7-H3 and inhibited the growth of B7-H3-expressing cancer cells, but not that of B7-H3-negative cancer cells, in vitro. Additionally, treatment with DS-7300a and DXd induced phosphorylated checkpoint kinase 1, a DNA damage marker, and cleaved PARP, an apoptosis marker, in cancer cells. Moreover, DS-7300a demonstrated potent in vivo antitumor activities in high-B7-H3 tumor xenograft models, including various tumor types of high-B7-H3 PDX models. Furthermore, DS-7300a was stable in circulation with acceptable pharmacokinetic profiles in monkeys, and well tolerated in rats and monkeys. DS-7300a exerted potent antitumor activities against B7-H3-expressing tumors in in vitro and in vivo models, including PDX mouse models, and showed acceptable pharmacokinetic and safety profiles in nonclinical species. Therefore, DS-7300a may be effective in treating patients with B7-H3-expressing solid tumors in a clinical setting.

Interaction of ONION2 ketoacyl CoA synthase with ketoacyl CoA reductase of rice.

BACKGROUND: Fatty acid elongases (FAEs), which catalyse elongation reactions of a carbon chain of very-long-chain fatty acids, play an important role in shoot development in rice. The elongation reactions consist of four sequential reactions catalysed by distinct enzymes, which are assumed to form an elongation complex. However, no interacting proteins of ONION1 (ONI1) and ONI2, which are ketoacyl CoA synthase catalyzing the first step and are required for shoot development in rice, are reported. METHODS AND RESULTS: In this study ketoacyl CoA reductase (KCR) that interacts with ONI1 and ONI2 was searched. A database search identified 10 KCR genes in the rice genome. Among the genes, the expression pattern of KCR1 was similar to that of ONI2. Yeast two-hybrid analysis showed interaction of ONI2 with KCR1, which was confirmed by GST pull-down assay. No interacting partner of ONI1 was identified. CONCLUSIONS: Our results suggest that ONI2 and KCR1 form an FAE complex that may play a role in biosynthesizing VLCFAs during shoot development.