High incidence and early onset of nivolumab-induced pneumonitis: four case reports and literature review.

BACKGROUND: Nivolumab, an anti-programmed cell death-1 (PD-1) monoclonal antibody used as an immune checkpoint inhibitor, is commonly employed for its anti-tumor effects against various types of malignant tumors. However, its administration is complicated by immune-related adverse events (irAEs), including pneumonitis. CASE PRESENTATION: We present a case series of four patients with malignant melanoma, non-small cell lung cancer, and hypopharyngeal carcinoma who demonstrated pneumonitis induced by nivolumab, and further review clinicopathological characteristics of these patients in comparison with those of previously reported patients with nivolumab-induced pneumonitis. In our series, 20% of patients who were treated with nivolumab developed pneumonitis, all of which occurred approximately 2 weeks after the initiation of nivolumab treatment. Prompt recognition of the nivolumab-induced pneumonitis allowed for successful resolution. Computed tomography scan images of the patients demonstrated predominantly cryptogenic organizing pneumonia patterns. All patients were males, who had been heavily treated with antitumor drugs prior to nivolumab. CONCLUSIONS: Our case series showed that nivolumab had a high incidence of drug-induced pneumonitis with early onset, supporting the need for renewed attention to nivolumab-induced pneumonitis, particularly in patients with a history of heavy antitumor treatments.

Effectiveness of nanoparticle albumin-bound paclitaxel plus carboplatin in non-small lung cancer patients with malignant pleural effusion.

Malignant pleural effusion (MPE) is a common complication occurring in cancer patients, and its management affects the prognosis of these patients. Preclinical and clinical studies have reported that treatment with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus carboplatin (CBDCA) is effective against intraperitoneal malignant tumors. To investigate the effectiveness of nab-paclitaxel plus CBDCA therapy for MPEs arising in patients with non-small cell lung cancer (NSCLC), we retrospectively analyzed the clinicopathological characteristics of 40 patients with stage IIIb or IV NSCLC who were treated with nab-paclitaxel plus CBDCA from 2013 to 2016. Out of 26 patients with MPEs who were treated with nab-paclitaxel plus CBDCA in this study, 21 patients (80.8%) had effective responses in MPEs; 6 of 21 patients exhibited complete responses (23.1%) and 15 of 21 had partial responses (57.7%). Kaplan-Meier survival curves and log-rank tests to evaluate the effectiveness of nab-paclitaxel plus CBDCA therapy against MPEs showed longer median progression-free survival (323 days vs. 26 days; p=0.009) and overall survival (not reached vs. 199 days; p=0.047) in patients with complete responses compared with those who achieved no response. There were no statistical differences between therapeutic effects on MPEs and those on systemic lesions. Nab-paclitaxel plus CBDCA therapy may be a preferred therapeutic option for patients with NSCLC who experience MPEs, and its effectiveness in treatment of MPEs may need to be evaluated separately from its therapeutic responses in systemic lesions.

Circulatory CNP Rescues Craniofacial Hypoplasia in Achondroplasia.

Achondroplasia is the most common genetic form of human dwarfism, characterized by midfacial hypoplasia resulting in occlusal abnormality and foramen magnum stenosis, leading to serious neurologic complications and hydrocephalus. Currently, surgery is the only way to manage jaw deformity, neurologic complications, and hydrocephalus in patients with achondroplasia. We previously showed that C-type natriuretic peptide (CNP) is a potent stimulator of endochondral bone growth of long bones and vertebrae and is also a potent stimulator in the craniofacial region, which is crucial for midfacial skeletogenesis. In this study, we analyzed craniofacial morphology in a mouse model of achondroplasia, in which fibroblast growth factor receptor 3 (FGFR3) is specifically activated in cartilage ( Fgfr3ach mice), and investigated the mechanisms of jaw deformities caused by this mutation. Furthermore, we analyzed the effect of CNP on the maxillofacial area in these animals. Fgfr3ach mice exhibited midfacial hypoplasia, especially in the sagittal direction, caused by impaired endochondral ossification in craniofacial cartilage and by premature closure of the spheno-occipital synchondrosis, an important growth center in craniomaxillofacial skeletogenesis. We crossed Fgfr3ach mice with transgenic mice in which CNP is expressed in the liver under the control of the human serum amyloid-P component promoter, resulting in elevated levels of circulatory CNP ( Fgfr3ach/SAP-Nppc-Tg mice). In the progeny, midfacial hypoplasia in the sagittal direction observed in Fgfr3ach mice was improved significantly by restoring the thickness of synchondrosis and promoting proliferation of chondrocytes in the craniofacial cartilage. In addition, the foramen magnum stenosis observed in Fgfr3ach mice was significantly ameliorated in Fgfr3ach/SAP-Nppc-Tg mice due to enhanced endochondral bone growth of the anterior intraoccipital synchondrosis. These results clearly demonstrate the therapeutic potential of CNP for treatment of midfacial hypoplasia and foramen magnum stenosis in achondroplasia.

Comparison of human mesenchymal stem cells derived from bone marrow, synovial fluid, adult dental pulp, and exfoliated deciduous tooth pulp.

Populations of pluripotent stem cells were isolated from bone marrow, synovial fluid, adult dental pulp, and exfoliated deciduous teeth and their multipotentiality properties compared. Osteogenic, chondrogenic, adipogenic, and neurogenic differentiation potentials were examined. Bone marrow mesenchymal stem cells (BMMSCs) and synovial fluid-derived cells (SFCs) showed the highest levels of osteogenesis as expressed by alkaline phosphatase (ALP) activity (0.54±0.094 U/mg protein and 0.57±0.039 U/mg protein, respectively; P=0.60) and by osteocalcin (BGLAP; determined by real-time RT-PCR). SFCs showed the highest levels of chondrogenesis as expressed by ALP activity (1.75±0.097 U/mg protein) and of COL2A1 and COL10A1 by real-time PCR. In terms of adipogenesis, lipid vesicles were observed in the BMMSCs and SFCs. Dental pulp stem cells (DPSCs) and stem cells from human exfoliated deciduous teeth (SHED) exhibited neurogenesis potential, as shown by increases in expression of class III ß-tubulin (TUBB3) and microtubule-associated protein 2 (MAP2) on RT-PCR. Variability was found in the differentiation potential corresponding to the tendency of the original tissue to differentiate. It is suggested that the cell type should be selected depending on the regenerative treatment regimen.

Clinical and biological significance of erlotinib therapy after pemetrexed in non-small cell lung cancer with wild-type EGFR.

Pemetrexed is a multi-targeted anti-folate agent that confers favorable benefits to patients with non-small cell lung cancer (NSCLC). However, the optimal use including treatment schedule of pemetrexed and other drugs in clinical practice remains to be determined, particularly for NSCLC with wild-type epidermal growth factor receptor (EGFR). The present study investigated a potential therapeutic strategy for NSCLC patients with wild-type EGFR who were treated with pemetrexed. To identify factors associated with a survival, medical record data from 130 patients were retrospectively reviewed, using the Kaplan-Meier method with log-rank test. Factors identified in the clinical analysis were further investigated within in vitro studies. Patients who underwent the treatment schedule of erlotinib at the time of progression after pemetrexed-based chemotherapy prolonged overall survival, compared to those treated with other schedules (p=0.010; hazard ratio, 0.418). This survival benefit was also observed in the treatment schedule of pemetrexed monotherapy and subsequent erlotinib (p=0.008; hazard ratio, 0.220). As a treatment at the time of progression after pemetrexed-based chemotherapy, erlotinib conferred a survival benefit when compared to docetaxel (p=0.024; hazard ratio, 0.377). The cell growth assay confirmed that treatment with pemetrexed followed by erlotinib significantly inhibited proliferation of NSCLC cells regardless of EGFR mutation status. In conclusion, use of erlotinib at the time of progression after pemetrexed therapy confers a survival benefit in NSCLC patients with wild-type EGFR. The result of this study provides an important clue to the optimal treatment schedule for NSCLC.

Adverse cardiovascular events predict survival benefit in non-small lung cancer patients treated with bevacizumab.

BACKGROUND: Bevacizumab is a monoclonal antibody against vascular endothelial growth factor (VEGF) that provides a survival benefit to patients with non-small cell lung cancer (NSCLC). However, the treatment is sometimes accompanied by life-threatening bleeding events, and studies have not yet identified factors that can predict outcomes for NSCLC patients receiving bevacizumab. METHODS: To identify prognostic factors for patients with NSCLC who are undergoing bevacizumab therapy, this study retrospectively investigated 34 consecutive patients with NSCLC treated with bevacizumab-containing chemotherapy. RESULTS: Adverse cardiovascular events, including hypertension and bleeding events, during bevacizumab therapy were observed in 18 patients (53%). Kaplan-Meier survival analyses and log-rank tests revealed that median overall survival was significantly better in patients who experienced adverse cardiovascular events than those who did not (442 versus 304 days; P=0.012). In the multivariate Cox proportional hazard model, the onset of adverse cardiovascular events was independently associated with a better overall survival. CONCLUSIONS: The onset of adverse cardiovascular events during bevacizumab therapy may be a favorable prognostic factor for patients with NSCLC. The results of this retrospective study warrant further large-scale prospective trials.

Phase 1 study of lenvatinib combined with carboplatin and paclitaxel in patients with non-small-cell lung cancer.

BACKGROUND: This dose-finding study evaluated lenvatinib, an oral multitargeted receptor tyrosine kinase inhibitor, in combination with carboplatin/paclitaxel in chemotherapy-naïve non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Patients received lenvatinib twice daily (BID) with carboplatin (area under the curve 6 mg ml(-1) min(-1), day 1)/paclitaxel (200 mg m(-2), day 1) every 3 weeks. The initial dose of lenvatinib was 6 mg BID. The primary end point was maximum tolerated dose (MTD) of lenvatinib. At the MTD, the cohort was expanded by 16 patients. Safety, pharmacokinetics, pharmacodynamics, and antitumor effects were evaluated. RESULTS: Twenty-eight patients were treated. At 6 mg BID, dose-limiting toxicities (DLTs) included febrile neutropenia/gingival infection (n=2). No DLTs occurred with 4 mg BID, the recommended MTD for the expansion. Common grade 3/4 toxicities included neutropenia, leukopenia, hypertension, and thrombocytopenia. The combination had no significant impact on individual drug pharmacokinetics. Response rate and median progression-free survival were 68% and 9.0 months, respectively, with 4 mg BID. In the plasma biomarker analysis, stromal cell-derived factor 1α, stem cell factor, and granulocyte colony-stimulating factor correlated with antitumor activity. CONCLUSION: The MTD for lenvatinib with carboplatin/paclitaxel is 4 mg BID in advanced NSCLC patients. This regimen demonstrated manageable tolerability and encouraging antitumor activity.

[Pulmonary venous obstruction after the Williams procedure for partial anomalous pulmonary venous connection].

A 54-year-old man was admitted to our hospital because of chest discomfort. Cardiac catheterization revealed partial anomalous pulmonary venous connection with an intact atrial septum. The right upper pulmonary vein (RUPV) drained into the upper segment of the superior vena cava (SVC). Using the Williams procedure, an atrial septal defect (ASD) was created and a fresh autologous pericardial patch was used to fashion a new pulmonary vein return route from SVC to the ASD. Although the patient was stable after the procedure, he was admitted again 6 months later because of obstruction of RUPV. At reoperation, it was found that the previous pulmonary vein route was obstructed and that the pericardial baffle had adhered to the atrial septum above the ASD. The shrunken and thickened pericardial baffle was removed and the orifice of the ASD was extensively enlarged, after which an expanded polytetrafluoroethylene (ePTFE) patch was used as a new baffle. After the reoperation, the patient's condition improved.

Identification of IGFBP-6 as an effector of the tumor suppressor activity of SEMA3B.

SEMA3B, a member of class 3 semaphorins, is a tumor suppressor. Competition with vascular endothelial growth factor (VEGF)165 explains a portion of the activity, whereas the VEGF-independent mechanism was not elucidated. We employed a microarray and screened for the genes whose expression was increased by SEMA3B in NCI-H1299 cells. Insulin-like growth factor-binding protein-6 (IGFBP-6), a tumor suppressor, showed greatest difference in the expression level. Introduction of IGFBP-6 cDNA reduced colony formation both on the dish surface and in soft agar. Insulin-like growth factor II, which antagonizes IGFBP-6, partly abrogated the effect. Inhibition of IGFBP-6 by small interfering RNA diminished the sub-G0/G1 population that was induced by SEMA3B and abrogated the growth suppressive effect of SEMA3B. We concluded that IGFBP-6 is the effector of tumor suppressor activity of SEMA3B in NCI-H1299 cells. It has been reported that beta-catenin suppresses the expression of IGFBP-6. Introduction of beta-catenin into the cells partly abrogated the growth suppressive effect of SEMA3B. Our result indicates that semaphorin signaling and beta-catenin signaling converge on IGFBP-6 and antithetically affect their functions.

Muir-Torre syndrome caused by partial duplication of MSH2 gene by Alu-mediated nonhomologous recombination.

We describe a 54-year-old man with a pedicled tumour on the neck. The surgical specimen revealed a sebaceous carcinoma. He belonged to a cancer-prone family susceptible to gastrointestinal cancer. Systemic evaluation for latent malignancies revealed early-stage colonic adenocarcinoma. These findings were compatible with Muir-Torre syndrome (MTS). Microsatellite instability was detected in the sebaceous carcinoma, suggesting a DNA mismatch repair gene mutation. Moreover, duplication of exon 7 generated a nonsense codon at codon 427 of the MSH2 gene causing truncation of MSH2 protein. Immunohistochemical analysis showed diminished MSH2 protein levels in the sebaceous carcinoma and colonic adenocarcinoma. To date, there have been no reports showing duplication of exon 7 of the MSH2 gene in MTS or hereditary nonpolyposis colorectal cancer kindreds. Furthermore, the present case indicates that the dermatologist plays an important role in the diagnosis of MTS and evaluation for latent malignancies.

Pregnancy achieved following IVF-ET after surgery for infertility with perforate transverse vaginal septum and incomplete septate uterus: case report.

Transverse vaginal septum is a rare congenital anomaly. Imperforate transverse vaginal septum causes marked clinical symptoms, and is diagnosed at a young age in most cases. Perforate transverse vaginal septum is difficult to detect due to the absence of symptoms. In this study, we report a case of a 33-year-old infertile female with a perforate transverse vaginal septum and incomplete septate uterus who had wished to bear a child for over ten years, and consulted our hospital. Transverse vaginal septum was considered to be an etiological factor for infertility. After surgery for transverse vaginal septum, in vitro fertilization achieved pregnancy.

Gefitinib for non-small-cell lung cancer patients with epidermal growth factor receptor gene mutations screened by peptide nucleic acid-locked nucleic acid PCR clamp.

This study was prospectively designed to evaluate a phase II study of gefitinib for non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. Clinical samples were tested for EGFR mutations by peptide nucleic acid-locked nucleic acid PCR clamp, and patients having EGFR mutations were given gefitinib 250 mg daily as the second treatment after chemotherapy. Poor PS patients omitted chemotherapy. Of 107 consecutive patients enrolled, samples from 100 patients were informative, and EGFR mutations were observed in 38 patients. Gefitinib was given to 27 patients with EGFR mutations, and the response rate was 78% (one complete response and 20 partial responses; 95% confidence interval: 58-93%). Median time to progression and median survival time (MST) from gefitinib treatment were 9.4 and 15.4 months, respectively. Grade 3 hepatic toxicity and skin toxicity were observed in one patient each. There were significant differences between EGFR mutations and wild-type patients in response rates (78 vs 14%, P = 0.0017), and MST (15.4 vs 11.1 months, P = 0.0135). A Cox proportional hazards model indicated that negative EGFR mutation was a secondary prognostic factor (hazards ratio: 2.259, P = 0.036). This research showed the need for screening for EGFR mutations in NSCLC patients.

Expansion of human CMV-specific cytotoxic T lymphocytes to a clinical scale: a simple culture system using tetrameric HLA-peptide complexes.

BACKGROUND: Recipients of allogeneic stem cell transplants (SCT) are at risk of human CMV infection during their immunocompromised period. The increasing number of reports of CMV isolates resistant to ganciclovir after transplantation has led us to attempt to develop alternative strategies for preventing or treating CMV infection. This study describes a system for generating sufficient numbers of CMV-specific cytotoxic T lymphocytes (CTL) for adoptive immunotherapy after SCT. METHODS: CMV-specific CTL were isolated from a single blood draw of a CMV-seropositive donor using PE-labeled HLA-A*0201/pp65(495-503) tetramers and anti-PE magnetic beads. A mixture of a tetramer-positive population and CD4(+) T lymphocytes was expanded to sufficient numbers for clinical application with IL-2 and immobilized anti-CD3 stimulation. RESULT: Starting from 50 mL of blood, we generated >10(7)/m(2) tetramer-positive CTL within 2 weeks. Flow cytometric analysis of expanded lymphocytes showed that purity of CMV peptide-specific CTL was >75%. Upon stimulation of HLA-A*0201-restricted CMV peptide, expanded CD8 T lymphocytes produced intracellular IFN-gamma. Purified CTL exhibited cytotoxic activity against CMV peptide-pulsed T2 cells and CMV-infected HLA-A*0201-positive fibroblasts, but not against HLA mismatched or uninfected target cells. Alloreactivity could be excluded in MLC. DISCUSSION: This simple, rapid culture system can be useful for adoptive immunotherapy after allogeneic SCT. We are now trying to adapt our laboratory scale study to a clinical scale study under good manufacturing practices (GMP) conditions.

[Off-pump coronary artery bypass grafting for severe acute coronary syndrome].

UNLABELLED: Off-pump coronary artery bypass grafting (off-pump CABG: OPCAB) has become a standard procedure, but the indication for the patients with severe acute coronary syndrome (ACS) has not been established. The purpose of this study is to evaluate the role of OPCAB for patients with acute myocardial infarction (AMI) and impending myocardial infarction (IMI). Clinical indication of OPCAB for acute coronary syndrome between November 1997 and December 2002, 14 patients diagnosed ACS out of 220 CABG cases underwent surgery. Twelve male and 2 female with a mean age of 66.3 +/- 7.5 were NYHA grade IV condition before surgery. Three of nine AMI cases and 4 of 5 IMI cases underwent OPCAB. Thirteen cases needed intra-aortic balloon pumping (IABP) support pre-operation, in 1 AMI and 2 IMI cases IABP had to be weaned during operation. The mean graft number was 2.6. Except one AMI case with severe cardiac damage, 13 cases were discharged in NYHA grade I-II condition. CONCLUSION: In early onset cases with still rising CK-MB, operative risk and result is difficult to evaluate pre-operatively. Equal results could be seen in IMI cases with no previous myocardial damage. We suggest, that in cases without severe myocardial damage, OPCAB could be one alternative treatment.

Tuberculous abdominal aortic pseudoaneurysm penetrating the left psoas muscle after BCG therapy for bladder cancer.

We describe a case of a 75-year-old man with abdominal aortic and right femoral tuberculous pseudoaneurysms 32 months after intravesical bacillus Calmette-Guerin therapy for bladder cancer. These aneurysms were probably brought on by systemic infection by Mycobacterium bovis. The infrarenal aorta and right common femoral artery were successfully replaced with an in situ expanded polytetrafluoroethylene graft. Tuberculous pseudoaneurysm after bacillus Calmette-Guerin therapy for malignancy is very rare, and we review the related literature.

Potential role of phosphodiesterase 7 in human T cell function: comparative effects of two phosphodiesterase inhibitors.

Even though the existence of phosphodiesterase (PDE) 7 in T cells has been proved, the lack of a selective PDE7 inhibitor has confounded an accurate assessment of PDE7 function in such cells. In order to elucidate the role of PDE7 in human T cell function, the effects of two PDE inhibitors on PDE7A activity, cytokine synthesis, proliferation and CD25 expression of human peripheral blood mononuclear cells (PBMC) were determined. Recombinant human PDE7A was obtained and subjected to cyclic AMP-hydrolysis assay. PBMC of Dermatophagoides farinae mite extract (Df)-sensitive donors were stimulated with the relevant antigen or an anti-CD3 monoclonal antibody (MoAb). PBMC produced IL-5 and proliferated in response to stimulation with Df, while stimulation with anti-CD3 MoAb induced CD25 expression and messenger RNA (mRNA) synthesis of IL-2, IL-4 and IL-5 in peripheral T cells. A PDE inhibitor, T-2585, which suppressed PDE4 isoenzyme with high potency (IC50 = 0.00013 microM) and PDE7A with low potency (IC50 = 1.7 microM) inhibited cytokine synthesis, proliferation and CD25 expression in the dose range at which the drug suppressed PDE7A activity. A potent selective inhibitor of PDE4 (IC50 = 0.00031 microM), RP 73401, which did not effectively suppress PDE7A (IC50 > 10 microM), inhibited the Df- and anti-CD3 MoAb-stimulated responses only weakly, even at 10 microM. PDE7 may play a critical role in the regulation of human T cell function, and thereby selective PDE7 inhibitors have the potential to be used to treat immunological and inflammatory disorders.

Possible involvement of a single histidine residue in the P-type Na+-ATPase of a facultatively anaerobic alkaliphile, Exiguobacterium aurantiacum.

Effect of various inhibitors on the P-type Na+-ATPase of a facultatively anaerobic alkaliphile, Exiguobacterium aurantiacum, was examined. The ATPase was extremely sensitive to p-chloromercuriphenylsulfonic acid, a modifier of SH-group. The enzyme was also sensitive to diethylpyrocarbonate, and analysis of the inhibition kinetics by the drug indicated that modification of a single histidine residue per ATPase molecule was sufficient to inactivate the enzyme.

Novel betacellulin derivatives. Separation of the differentiation activity from the mitogenic activity.

Betacellulin (BTC) is a member of the epidermal growth factor family. It has two biological activities: mitogenic activity in fibroblasts and vascular smooth muscle cells, and differentiation activity for the differentiation of pancreatic acinar AR42J cells into insulin-secreting cells. The previous finding that recombinant BTC promotes the neogenesis of beta-cells in a mouse model supports the possibility that BTC is a therapeutic protein. However, the mitogenic activity of BTC may not be needed for differentiation into beta-cells and may cause a side effect in clinical use. We prepared several derivatives of BTC to segregate the two activities, to decrease the mitogenic activity, and to maintain the differentiation activity. We succeeded in obtaining BTC derivatives segregated by the two biological activities by preparing truncated-type derivatives. A derivative of BTC, BTC24-76, with a truncated N-terminal 23 amino acids and C-terminal 4 amino acids, was 2.5-fold more active in differentiation and had one-tenth of the mitogenic activity. The derivatives described in the present study should be helpful in future applications as therapeutic proteins and in basic research for discovery of a BTC-specific receptor.

Receptor specificities of human respiroviruses.

Through their hemagglutinin-neuraminidase glycoprotein, parainfluenza viruses bind to sialic acid-containing glycoconjugates to initiate infection. Although the virus-receptor interaction is a key factor of infection, the exact nature of the receptors that human parainfluenza viruses recognize has not been determined. We evaluated the abilities of human parainfluenza virus types 1 (hPIV-1) and 3 (hPIV-3) to bind to different types of gangliosides. Both hPIV-1 and hPIV-3 preferentially bound to neolacto-series gangliosides containing a terminal N-acetylneuraminic acid (NeuAc) linked to N-acetyllactosamine (Galbeta1-4GlcNAc) by the alpha2-3 linkage (NeuAcalpha2-3Galbeta1-4GlcNAc). Unlike hPIV-1, hPIV-3 bound to gangliosides with a terminal NeuAc linked to Galbeta1-4GlcNAc through an alpha2-6 linkage (NeuAcalpha2-6Galbeta1-4GlcNAc) or to gangliosides with a different sialic acid, N-glycolylneuraminic acid (NeuGc), linked to Galbeta1-4GlcNAc (NeuGcalpha2-3Galbeta1-4GlcNAc). These results indicate that the molecular species of glycoconjugate that hPIV-1 recognizes are more limited than those recognized by hPIV-3. Further analysis using purified gangliosides revealed that the oligosaccharide core structure is also an important element for binding. Gangliosides that contain branched N-acetyllactosaminoglycans in their core structure showed higher avidity than those without them. Agglutination of human, cow, and guinea pig erythrocytes but not equine erythrocytes by hPIV-1 and hPIV-3 correlated well with the presence or the absence of sialic acid-linked branched N-acetyllactosaminoglycans on the cell surface. Finally, NeuAcalpha2-3I, which bound to both viruses, inhibited virus infection of Lewis lung carcinoma-monkey kidney cells in a dose-dependent manner. We conclude that hPIV-1 and hPIV-3 preferentially recognize oligosaccharides containing branched N-acetyllactosaminoglycans with terminal NeuAcalpha2-3Gal as receptors and that hPIV-3 also recognizes NeuAcalpha2-6Gal- or NeuGcalpha2-3Gal-containing receptors. These findings provide important information that can be used to develop inhibitors that prevent human parainfluenza virus infection.

Inhibition of human parainfluenza virus type 1 sialidase by analogs of 2-deoxy-2,3-didehydro-N-acetylneuraminic acid.

Eleven novel analogs of 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (Neu5Ac2en) modified at the C-4 and C-9 positions were designed and tested for their ability to inhibit sialidase of human parainfluenza virus type 1 (hPIV-1). The analogs modified by the cyanomethyl, amidinomethyl, and thiocarbamoylmethyl groups at the C-4 position exhibited potent inhibition against hPIV-1 sialidase compared with Neu5Ac2en. The most effective compound was thiocarbamoylmethyl analog (4-O-thiocarbamoylmethyl-Neu5Ac2en). The activity of 4-O-thiocarbamoylmethyl-Neu5Ac2en causing 50% enzyme inhibition at a concentration of approximately 1.0x10(-5) M was 30-fold larger than Neu5Ac2en. While, the analogs of Neu5Ac2en modified by the azido and N-acetyl groups at the C-9 showed a decrease in inhibition of sialidase compared with the 9-hydroxy analogs. In addition, 4-O-thiocarbamoylmethyl-Neu5Ac2en strongly inhibited hPIV-1 infections of Lewis lung carcinoma-monkey kidney cells in comparison with Neu5Ac2en. The present findings would provide useful information for the development of anti-human parainfluenza virus compounds.