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Biomedical subjects

Koichi Kobayashi

Publications and source records attributed to Koichi Kobayashi.

At least 19 recordsLinked to original sources
PubMed2006

Phase II trial of gemcitabine and docetaxel in patients with completely resected stage IIA-IIIA non-small-cell lung cancer.

BACKGROUND: Few clinical phase II studies using non-platinum doublet as adjuvant chemotherapy following complete resection of non-small-cell lung cancer (NSCLC) have been published, so this clinical study was designed to evaluate the toxicity profile and efficacy of the non-platinum doublet of docetaxel (DOC) + gemcitabine (GEM). METHODS: Eligibility criteria included completely resected NSCLC, pathological stage II or IIIA, younger than 76 years old, and performance status 0-1. Treatment consisted of DOC 60 mg/m2 on day 8, and GEM 1,000 mg/m2 on days 1, 8, and 15 every 4 weeks (4 cycles). The GEM dosage was decreased to 800 mg/m2 after the initial 21 patients because 3 patients developed interstitial lung disease (ILD). RESULTS: Thirty-five patients (male/female 21/14) were enrolled. The median age was 62 years (range 47-74), with five (14.3%) over the age of 70. Performance status was 0 in 34 patients. The diagnosis was ad in 28 patients, sq in 6, and adsq in 1. The pathological stage was IIA in 5 patients, IIB in 1 and stage IIIA in 29 (82.9%). All patients underwent at least one cycle of chemotherapy, with 29 patients completing three cycles of chemotherapy and 23 (66%) had four cycles. The main grade 3/4 toxicities comprised neutropenia (n = 21, 60%), thrombocytopenia (n = 3, 8.6%), anorexia (n = 4, 11.4%), and ILD (n = 3, 8.6%), which responded well to corticosteroids. There were no treatment-related deaths. The 4-year recurrence-free survival rate was 42.9%, and the 4-year survival rate was 65.8%. CONCLUSIONS: The non-platinum doublet regimen of DOC + GEM as adjuvant chemotherapy following complete resection of NSCLC is feasible, with good compliance, the only problem being ILD.

Aged↗
PubMed2006

Therapeutic angiogenesis using novel vascular endothelial growth factor-E/human placental growth factor chimera genes.

BACKGROUND: Vascular endothelial growth factor-A (VEGF-A) promotes angiogenesis but causes adverse side effects such as edema or tissue inflammation. VEGF-E, found in the genome of the Orf virus, specifically binds to VEGF receptor-2 and shows mitotic activity on endothelial cells. Recently, we created two forms of VEGF-E and human placental growth factor (PlGF) chimera genes (VEGF-E chimera #9 and VEGF-E chimera #33), which are humanized genes with VEGF-E function but showing less antigenicity. METHODS AND RESULTS: We examined potential proangiogenic activities of these chimera genes. Four types of expression plasmids (pCDNA3.1-LacZ, phVEGF-A, pVEGF-Echimera#9, and pVEGF-Echimera#33) were administered in a rat model of hindlimb ischemia. Either pVEGF-Echimera#9, pVEGF-Echimera#33, or phVEGF-A significantly increased the ratio of ischemic/normal hindlimb blood-flow compared with the control pCDNA3.1-LacZ treated group (by 1.5-fold, 1.5-fold, and 1.4-fold, respectively, P<0.05). Histochemical staining by alkaline phosphatase also revealed that either pVEGF-Echimera#9, pVEGF-Echimera#33, or phVEGF-A increased the capillary density compared with the pCDNA3.1-LacZ treated group (1.4-fold, 1.5-fold, and 1.5-fold, respectively, P<0.05). Furthermore, immunostaining for anti-ED1 revealed that fewer macrophages had infiltrated in both pVEGF-Echimera#9 and pVEGF-Echimera#33 groups compared with the phVEGF-A group (P<0.05). CONCLUSIONS: Novel VEGF-E/human PlGF chimera genes, pVEGF-Echimera#9, and pVEGF-Echimera#33 significantly stimulated angiogenesis in response to tissue ischemia to an almost identical extent to that induced by phVEGF-A with fewer tissue inflammation responses.

Animals↗
PubMed2006

Sepsis-induced suppression of lung innate immunity is mediated by IRAK-M.

Sepsis results in a state of relative immunosuppression, rendering critically ill patients susceptible to secondary infections and increased mortality. Monocytes isolated from septic patients and experimental animals display a "deactivated" phenotype, characterized by impaired inflammatory and antimicrobial responses, including hyporesponsiveness to LPS. We investigated the role of the LPS/TLR4 axis and its inhibitor, IL-1 receptor-associated kinase-M (IRAK-M), in modulating the immunosuppression of sepsis using a murine model of peritonitis-induced sepsis followed by secondary challenge by intratracheal Pseudomonasaeruginosa. Septic mice demonstrated impaired alveolar macrophage function and increased mortality when challenged with intratracheal Pseudomonas as compared with nonseptic controls. TLR2 and TLR4 expression was unchanged in the lung following sepsis, whereas levels of IRAK-M were upregulated. Macrophages from IRAK-M-deficient septic mice produced higher levels of proinflammatory cytokines ex vivo and greater costimulatory molecule expression in vivo as compared with those of their WT counterparts. Following sepsis and secondary intrapulmonary bacterial challenge, IRAK-M(-/-) animals had higher survival rates and improved bacterial clearance from lung and blood compared with WT mice. In addition, increased pulmonary chemokine and inflammatory cytokine production was observed in IRAK-M(-/-) animals, leading to enhanced neutrophil recruitment to airspaces. Collectively, these findings indicate that IRAK-M mediates critical aspects of innate immunity that result in an immunocompromised state during sepsis.

Animals↗
PubMed2006

Clinical evaluation of chemosensitivity testing for patients with unresectable non-small cell lung cancer (NSCLC) using collagen gel droplet embedded culture drug sensitivity test (CD-DST).

PURPOSE: In the present study, we prospectively evaluated the clinical feasibility and efficacy of collagen gel droplet embedded culture drug sensitivity test (CD-DST) in unresectable non-small cell lung cancer (NSCLC) without previous treatment. EXPERIMENTAL DESIGN: Eighty patients with unresectable NSCLC, aged less than 81 years old, PS 0-1, and with evaluable tumor lesions, entered the study. If the patient had CD-DST active drugs, more than three cycles of chemotherapy containing these drugs were administered. If the patient did not have CD-DST active drugs, the patient could choose any treatment including best supportive care. RESULTS: Of the 80 patients in this study, CD-DST yielded results successfully in 49 patients (61.3%). CD-DST active drugs were present in 22 patients, and significantly more female patients had in vitro active anticancer agents than male (P=0.0008). All of the patients with CD-DST active agents received chemotherapy including these agents. In these patients, the response rate was 72.7%, and median survival was 15.0 months. In the patients without CD-DST active agents, 11 patients received standard, empirical chemotherapy. In these patients, response rate was 0%, and median survival was 6.0 months. CONCLUSIONS: The results show that CD-DST is capable of selecting the responders and the respective optimal regimens, and also delineating the patients less likely benefit from treatment.

Adult↗
PubMed2006

Use of hemoglobin vesicles during cardiopulmonary bypass priming prevents neurocognitive decline in rats.

BACKGROUND: Homologous blood use is considered to be the gold standard for cardiopulmonary bypass (CPB) priming in infants despite exposure of the patient to potential cellular and humoral antigens. However, the use of hemoglobin vesicles (HbVs), artificial oxygen carriers that encapsulate a concentrated hemoglobin solution within phospholipid bilayer membranes, for CPB priming may prevent neurocognitive decline in infants. The goal of this study was to determine whether HbV use offsets hemodilution caused by patient/priming volume-mismatched CPB and thereby prevents the development of postoperative neurocognitive deficits. METHODS AND RESULTS: CPB was established in 28 male Sprague-Dawley rats (age, 14 to 16 weeks; weight, 450 grams) after cannulation of the tail artery and right atrium. The animals were randomly assigned to 1 of 3 groups: sham surgery (n=9), HbV (-) prime (n=10), or HbV (+) prime (n=9). CPB was conducted for 90 minutes at 200 mL/kg per minute. The hematocrit during CPB was 10.0+/-1.2% in the HbV (+) prime group and 9.9+/-1.3% in the HbV (-) prime group (P=not significant). Learning and memory function were evaluated using 2 different maze tests (Maze-1 and Maze-2, in which the arrival times to the target were measured on the first, third, fifth, and seventh postoperative days). Learning and memory function were significantly better in the HbV (+) prime group than in the HbV (-) prime group (Maze-1, P=0.012; Maze-2, P=0.042); there was no difference between the HbV (+) prime and the sham surgery group. CONCLUSIONS: The use of HbV for CPB priming may serve as a substitute for homologous blood to prevent the unacceptable hemodilution and contribute to maintenance of intact neurocognitive function.

Animals↗
PubMed2006

Membrane lipid alteration during phosphate starvation is regulated by phosphate signaling and auxin/cytokinin cross-talk.

During phosphate (Pi) starvation in plants, membrane phospholipid content decreases concomitantly with an increase in non-phosphorus glycolipids. Although several studies have indicated the involvement of phytohormones in various physiological changes upon Pi starvation, the regulation of Pi-starvation induced membrane lipid alteration remains unknown. Previously, we reported the response of type B monogalactosyl diacylglycerol synthase genes (atMGD2 and atMGD3) to Pi starvation, and suggested a role for these genes in galactolipid accumulation during Pi starvation. We now report our investigation of the regulatory mechanism for the response of atMGD2/3 and changes in membrane lipid composition to Pi starvation. Exogenous auxin activated atMGD2/3 expression during Pi starvation, whereas their expression was repressed by cytokinin treatment in the root. Moreover, auxin inhibitors and the axr4 aux1 double mutation in auxin signaling impaired the increase of atMGD2/3 expression during Pi starvation, showing that auxin is required for atMGD2/3 activation. The fact that hormonal effects during Pi starvation were also observed with regard to changes in membrane lipid composition demonstrates that both auxin and cytokinin are indeed involved in the dynamic changes in membrane lipids during Pi starvation. Phosphite is not metabolically available in plants; however, when we supplied phosphite to Pi-starved plants, the Pi-starvation response disappeared with respect to both atMGD2/3 expression and changes in membrane lipids. These results indicate that the observed global change in plant membranes during Pi starvation is not caused by Pi-starvation induced damage in plant cells but rather is strictly regulated by Pi signaling and auxin/cytokinin cross-talk.

Arabidopsis↗
PubMed2006

PEGylated albumin-heme as an oxygen-carrying plasma expander: Exchange transfusion into acute anemia rat model.

Poly(ethylene glycol) (PEG) conjugated recombinant human serum albumin (HSA) incorporating the synthetic iron-porphyrin (FeP) [PEGylated albumin-heme, PEG(HSA-FeP)] is a unique albumin-based oxygen carrier as a red blood cell (RBC) substitute. The physiological responses to an exchange transfusion with PEG(HSA-FeP) into an acute anemia rat model were investigated. After a 65% isovolemic hemodilution with HSA, a 30% volume of the circulatory blood was withdrawn, affording a hemorrhaged state. The circulation parameters, blood parameters, renal cortical oxygen partial pressure [PtO(2)(R)], and muscle tissue oxygen partial pressure [PtO(2)(M)] were continuously monitored. The intravenous infusion of PEG(HSA-FeP) restored the reduced levels of the mean arterial pressure, heart rate, respiration rate, mixed venous PO(2), and arterial PCO(2). The increased arterial PO(2) and pH also returned to their basal values. These effects were almost to the same extent as those observed after the administration of the RBC suspension. The relatively low recovery in PtO(2)(R) and PtO(2)(M) might be due to the Langmuir-type oxygen binding profile of PEG(HSA-FeP) (Hill coefficient: 1.0). All the animals survived during the experiments. In contrast, those injected with HSA died within 41 min. The PEG(HSA-FeP) solution is an oxygen-carrying plasma expander which can be used as a resuscitative fluid for hemorrhagic shock.

Acute Disease↗
PubMed2006

Combination of in vivo angiopoietin-1 gene transfer and autologous bone marrow cell implantation for functional therapeutic angiogenesis.

OBJECTIVE: Autologous bone marrow mononuclear cell (BM-MNC) implantation into ischemic tissues promotes angiogenesis, but a large amount of marrow aspiration is required, which is a major clinical limitation. Angiopoietin-1 (Ang-1) is requisite for vascular maturation during angiogenesis. We examined the impacts of combinatorial Ang-1 gene transfer and low-dose autologous BM-MNC implantation on therapeutic angiogenesis in a rabbit model of hind limb ischemia. METHODS AND RESULTS: Rabbits were divided into 4 groups: phosphate-buffered saline (control), 500 microg Ang-1 plasmid (Ang-1), 1 x 10(6) autologous BM-MNCs (BMC), and Ang-1 plasmid plus BM-MNCs (combination). The Ang-1 group had a greater angiographic score and capillary density compared with the control (P<0.05), but the Ang-1 gene therapy alone did not improve transcutaneous oxygen pressure (TcO2) and skin ulcer score. However, the combination group showed a significant improvement in not only angiographic score and capillary density (P<0.05) but also TcO2 (P<0.05) and skin ulcer score. These efficacies were greater in the combination group compared with the BMC group. CONCLUSIONS: This Ang-1 gene and BM-MNC combination therapy enhances not only quantitative but also qualitative angiogenesis in ischemic tissues. Moreover, the combination therapy will enable a reduction in the amount of BM aspiration required for significant therapeutic angiogenesis.

Angiography↗
PubMed2006

ADAM28 is overexpressed in human non-small cell lung carcinomas and correlates with cell proliferation and lymph node metastasis.

ADAM (a disintegrin and metalloproteinases) are a recently discovered gene family of proteins with sequence similarity to the reprolysin family of snake venom metalloproteinases, and about one-third of the family members have the catalytic site consensus sequence in their metalloproteinase domains. We screened the mRNA expression of 11 different ADAM species with putative metalloproteinase activity in human non-small cell lung carcinomas by RT-PCR, and found that prototype membrane-anchored ADAM28 (ADAM28m) and secreted ADAM28 (ADAM28s) are predominantly expressed in the carcinoma tissues. Real-time quantitative PCR demonstrated that the expression levels of ADAM28m and ADAM28s are significantly 16.8-fold and 9.0-fold higher in the carcinomas than in the non-carcinoma tissues, respectively. In addition, the expression levels of ADAM28m and ADAM28s were significantly higher in the carcinomas with >30 mm in diameter than in those < or =30 mm. The expression levels were also significantly higher in the carcinomas with lymph node metastasis than in those without metastasis. MIB1-positive cell index of the carcinomas had a direct correlation with the expression levels of ADAM28m and ADAM28s (r = 0.667, p < 0.001 and r = 0.535, p < 0.01, respectively). In situ hybridization and immunohistochemistry demonstrated that ADAM28 is expressed predominantly in the carcinoma cells. Immunoblot analysis showed the activated form of ADAM28 in the carcinoma tissues. These data demonstrate for the first time that ADAM28 is overexpressed and activated in human non-small cell lung carcinomas, and suggest the possibility that ADAM28 plays a role in cell proliferation and progression of the human lung carcinomas.

ADAM Proteins↗
PubMed2006

Effects of lumbar sympathetic ganglion block for a patient with amyotrophic lateral sclerosis (ALS).

A 59-year-old man with amyotrophic lateral sclerosis (ALS) received lumbar epidural and sympathetic ganglion blocks to increase regional blood flow and improve his clinical symptoms. After a lumbar epidural block (0.5% mepivacaine), the skin temperature of his affected lower extremities rose by 7.0 degrees C and became close to that of the intact side, and the distance he was able to walk with his cane increased from 2 to 8 m. The clinical effects produced by the lumbar sympathetic ganglion block (99.5% alcohol) were sustained for approximately 8 weeks after the first block and for approximately 6 weeks after the second block. There were no particular adverse effects or complications associated with these nerve block procedures. Epidural and sympathetic ganglion blocks for an ALS patient, albeit their effects are of a transient nature, may improve related clinical symptoms, and were thought to play a contributory role in improving our patient's quality of life.

Amyotrophic Lateral Sclerosis↗
PubMed2006

Long-term survival after incomplete resection of immunohistochemically diagnosed T0N1 lung cancer: report of a case.

A 63-year-old man who had undergone resection of colon cancer 15 years previously was found to have a right hilar mass on chest X-ray, and an elevated serum carcinoembryonic antigen level. The hilar lymph nodes were resected with the right upper lobe, and the initial diagnosis was colon cancer metastasis to the right hilar lymph nodes. Although the resection was incomplete, and no additional treatment was given, the patient remained free of recurrence for 10 years. This prompted us to reconsider our diagnosis using immunohistochemistry. The resected lymph nodes were found to be positive for thyroid transcription factor 1 (TTF-1) and cytokeratin 7, and negative for surfactant apoprotein (SAP), cytokeratin 20, and napsin A. The neuroendocrine markers and thyroglobulin were also negative. These findings led us to diagnose T0N1 lung cancer. There are reports of patients with clinical T0N1,2 lung cancer having exceptionally good prognoses despite noncurative treatment; however, to our knowledge, this is the first case of a patient with T0N1 lung cancer diagnosed by immunohistochemistry, with a good prognosis despite incomplete resection. In this case, TTF-1 and cytokeratin staining was particularly helpful in the differential diagnosis.

Adenocarcinoma↗
PubMed2006

Early pulmonary resection for Mycobacterium avium complex lung disease treated with macrolides and quinolones.

BACKGROUND: The purpose of this study was to examine the postoperative outcomes of patients with Mycobacterium avium complex (MAC) lung lesions persisting despite treatment with multiple antibiotics. METHODS: Patients with localized pulmonary lesions persisting despite extensive state-of-the art antimicrobial chemotherapy became candidates for surgical resection. Twenty-two patients who were expected to retain sufficient postoperative pulmonary function were included in this study. These patients received chemotherapy for 2 to 37 months (mean, 17). Surgical procedures were lobectomy (n = 15), segmentectomy (n = 4), and partial lung resection (n = 6). Three patients underwent bilateral resections. RESULTS: Mycobacterium avium complex causing bronchiectasis or cavitary lesions was detected preoperatively in all 22 patients. There was no major operative morbidity or mortality. Postoperative chemotherapy was continued for 6 to 35 months. All patients were alive and well at follow-ups ranging from 6 to 164 months (median, 46). Both vital capacity and forced expiratory volume in 1 second after surgery were maintained at 89% and 84% of the preoperative values, respectively. Mycobacterium avium complex disappeared from sputum after surgery in all patients. In 1 patient, 4 months after resection of a cavitary lesion, MAC-positive sputum presumed to be from the contralateral lung lesion became negative during continuation of chemotherapy. CONCLUSIONS: The long-term outcomes of patients operated on for MAC resistant to antimicrobial chemotherapy were excellent. For such patients, we recommend surgery before the disease becomes exceedingly advanced and nonresectable. Additionally, in extensive disease, the excision of large cavitary bacterial foci may assist the medical management of contralateral lesions.

Adult↗
PubMed2006

Percutaneous cryoablation of small pulmonary malignant tumors under computed tomographic guidance with local anesthesia for nonsurgical candidates.

OBJECTIVE: Cryoablation of pulmonary metastases might be a useful therapy for nonsurgical candidates. METHODS: The procedure was performed after achievement of local anesthesia for 35 tumors in 20 patients (12 male and 8 female patients; mean age, 57 years). The primary end point was the safety and feasibility of cryoablation, and the secondary end point was tumor control assessed by follow-up dynamic computed tomographic scanning performed every 3 months. RESULTS: Of the 22 sessions of cryoablation, pneumothorax occurred in 11, hemoptysis occurred in 8, and there was 1 case of phrenic nerve palsy. The mean hospital stay was 2.6 days. There was local recurrence of 7 (20%) tumors in 7 (35%) patients during a 9- to 28-month (median, 21 months) follow-up period. One-year survival according to the Kaplan-Meier method was 89.4%. CONCLUSION: Percutaneous cryoablation therapy for metastatic lung tumors is feasible and minimally invasive, with satisfactory local control.

Adult↗
PubMed2006

Hemoglobin-vesicles as a transfusion alternative.

Phospholipid vesicles or liposomes encapsulating purified and concentrated human hemoglobin (Hb-vesicle, HbV) have been developed as a transfusion alternative. They are void of blood-type antigens and infectious viruses; they are stable and suitable for long-term storage. The cellular structure of HbV (particle diameter, ca. 250 nm) prevents direct contact of Hb with the blood components and the endothelial lining shielding cells from the side effects of Hb molecules. Microcirculatory observations show that the cellular structure of HbV is important to control reactions with endothelium-derived vasorelaxation factors. Animal studies of extreme hemodilution and resuscitation from hemorrhagic shock attest to the sufficient oxygen transporting capacity of HbV. Studies of biodistribution and metabolism reveal that HbVs are captured eventually in the reticuloendothelial system, and degraded within one week. In a joint collaboration partnership of academia, a biotech venture company and a corporation, we plan to produce HbV with good manufacturing practices, and to start preclinical and, finally, clinical trials within a few years.

Animals↗
PubMed2006

Acute 40 percent exchange-transfusion with hemoglobin-vesicles (HbV) suspended in recombinant human serum albumin solution: degradation of HbV and erythropoiesis in a rat spleen for 2 weeks.

BACKGROUND: Hemoglobin-vesicles (HbVs; diameter, 251 +/- 81 nm) are artificial O(2) carriers. Their efficacy for acute exchange transfusion has been characterized in animal models. However subsequent profiles of recovery involving the degradation of HbV in the reticuloendothelial system (RES) and hematopoiesis remain unknown. STUDY DESIGN AND METHODS: Isovolemic 40 percent exchange transfusion was performed in 60 male Wistar rats with HbV suspended in 5 g per dL recombinant human serum albumin (rHSA; HbV/rHSA, [Hb] = 8.6 g/dL), stored rat RBCs suspended in rHSA (sRBC/rHSA), or rHSA alone. Hematological and plasma biochemical analyses and histopathological examination focusing on the spleen were conducted for the subsequent 14 days. RESULTS: The reduced hematocrit (Hct) level (26%) for the HbV/rHSA and rHSA groups returned to its original level (43%) in 7 days. Plasma erythropoietin was elevated in all groups: the rHSA group showed the highest value on Day 1 (321 +/- 123 mIU/mL) relating to the anemic conditions (HbV/rHSA, 153 +/- 22; sRBC/rHSA, 63 +/- 7; baseline, 21 +/- 3). Simultaneously, splenomegaly occurred in all the groups as HbV/rHSA > rHSA > sRBC/rHSA. Histopathologically, the accumulated HbV in the spleen was undetectable by Day 14, but hemosiderin was deposited in slight quantities for both the HbV/rHSA and sRBC/rHSA groups. Considerable amounts of erythroblasts were apparent in the spleens of both the rHSA and the HbV/rHSA groups. CONCLUSION: HbVs were phagocytized and degraded in RES, a physiological compartment for the degradation of RBCs, and the elevated erythropoietic activity resulted in the complete recovery of Hct within 7 days in the rat model.

Animals↗
PubMed2006

NF-kappa B-inducing kinase regulates selected gene expression in the Nod2 signaling pathway.

The innate immune system surveys the extra- and intracellular environment for the presence of microbes. Among the intracellular sensors is a protein known as Nod2, a cytosolic protein containing a leucine-rich repeat domain. Nod2 is believed to play a role in determining host responses to invasive bacteria. A key element in upregulating host defense involves activation of the NF-kappaB pathway. It has been suggested through indirect studies that NF-kappaB-inducing kinase, or NIK, may be involved in Nod2 signaling. Here we have used macrophages derived from primary explants of bone marrow from wild-type mice and mice that either bear a mutation in NIK, rendering it inactive, or are derived from NIK-/- mice, in which the NIK gene has been deleted. We show that NIK binds to Nod2 and mediates induction of specific changes induced by the specific Nod2 activator, muramyl dipeptide, and that the role of NIK occurs in settings where both the Nod2 and TLR4 pathways are activated by their respective agonists. Specifically, we have linked NIK to the induction of the B-cell chemoattractant known as BLC and suggest that this chemokine may play a role in processes initiated by Nod2 activation that lead to improved host defense.

Animals↗