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Heterotopic pancreas (HP) is rarely recognized during surgery. Many reports concerning this anomaly are simple case reports. We herein review our experiences with HP. We retrospectively investigated cases of HP from April 1975 to September 2006. We discussed the frequencies in the laparotomized patients, and patient's age, gender, operative indication, location of HP, post-operative diagnosis and pathology. A total of 12 patients with HP, 3 boys and 9 girls, aged 1 day to 10 years of age were investigated. Ten patients had one pattern of HP and the remaining two had more than one. The locations of the HP were as follows: Meckel's diverticulum, 4; stomach, 3; duodenum, 3; jejunum, 3; and ileum, 2. Only in one patient HP had caused an intussusception. The remaining 11 cases were identified incidentally during the operation. In 11 of 12 patients, HP was removed without post-operative complications. Classification of pathologies according to Heinrich is as follows: type I, 4; type II, 4; type III, 2 and unknown, 2. Patients with HP are usually asymptomatic. However, HP caused an intussusception in our series. Incidental HPs should be removed whenever identified during laparotomy. [ABSTRACT FROM AUTHOR]

HIV-1 protease inhibitors (PIs), such as darunavir (DRV), are the key component of antiretroviral therapy. However, HIV-1 often acquires resistance to PIs. Here, seven novel PIs were synthesized, by introducing single atom changes such as an exchange of a sulfur to an oxygen, scission of a single bond in P2′-cyclopropylaminobenzothiazole (or -oxazole), and/or P1-benzene ring with fluorine scan of mono- or bis-fluorine atoms around DRV's scaffold. X-ray structural analyses of the PIs complexed with wild-type Protease (PRWT) and highly-multi-PI-resistance-associated PRDRVRP51 revealed that the PIs better adapt to structural plasticity in PR with resistance-associated amino acid substitutions by formation of optimal sulfur bond and adaptation of cyclopropyl ring in the S2′-subsite. Furthermore, these PIs displayed increased cell permeability and extreme anti-HIV-1 potency compared to DRV. Our work provides the basis for developing novel PIs with high potency against PI-resistant HIV-1 variants with a high genetic barrier. [ABSTRACT FROM AUTHOR]

Tipranavir (TPV), a protease inhibitor (PI) inhibiting the enzymatic activity and dimerization of HIV-1 protease, exerts potent activity against multi-PI-resistant HIV-1 isolates. When a mixture of 11 multi-PI-resistant (but TPV-sensitive) clinical isolates (HIV11MIX), which included HIVB and HIVC, was selected against TPV, HIV11MIX rapidly (by 10 passages [HIV11MIXP10]) acquired high-level TPV resistance and replicated at high concentrations of TPV. HIV11MIXP10 contained various amino acid substitutions, including I54V and V82T. The intermolecular FRET-based HIV-1 expression assay revealed that TPV's dimerization inhibition activity against cloned HIVB (cHIVB) was substantially compromised. The introduction of I54V/V82T into wild-type cHIVNL4-3 (cHIVNL4-3154V/V82T) did not block TPV's dimerization inhibition or confer TPV resistance. However, the introduction of I54V/V82T into cHIVB (cHIVBl54V/V82T) compromised TPV's dimerization inhibition and cHIVB 154V/V82T proved to be significantly TPV resistant. L24M was responsible for TPV resistance with the cHIVc genetic background. The introduction of L24M into CHIVNL4-3 (CHIVNL4-3124M) interfered with TPV's dimerization inhibition, while L24M increased HIV-1's susceptibility to TPV with the HIVNL4-3genetic background. When selected with TPV, cHIVNL4-3154V/V82T most readily developed TPV resistance and acquired E34D, which compromised TPV's dimerization inhibition with the HIVNL4-3 genetic background. The present data demonstrate that certain amino acid substitutions compromise TPV's dimerization inhibition and confer TPV resistance, although the loss of TPV's dimerization inhibition is not always associated with significantly increased TPV resistance. The findings that TPV's dimerization inhibition is compromised with one or two amino acid substitutions may explain at least in part why the genetic barrier of TPV against HIV-1's development of TPV resistance is relatively low compared to that of darunavir. [ABSTRACT FROM AUTHOR]

The discovery of CCR5 as a HIV-1 co-receptor unfolded the cryptic and complicated process of HIV-1 cellular entry and has provided more than a few entry steps as possible modalities for effective viral intervention. The proof-of-principle has already been established for the use of entry inhibitors against HIV-1 and there is a cautious optimism that several CCR5 inhibitors might soon be added to our armamentarium for therapy of HIV-1 infection. [Copyright &y& Elsevier]

Designing non-natural antibody formats is a practical method for developing highly functional next-generation antibody drugs, particularly for improving the therapeutic efficacy of cancer treatments. One approach is constructing bispecific antibodies (bsAbs). We previously reported a functional humanized bispecific diabody (bsDb) that targeted epidermal growth factor receptor and CD3 (hEx3-Db). We enhanced its cytotoxicity by constructing an Fc fusion protein and rearranging order of the V domain. In this study, we created an additional functional bsAb, by integrating the molecular formats of bsAb and high-affinity mutants previously isolated by phage display in the form of Fv. Introducing the high-affinity mutations into bsDbs successfully increased their affinities and enhanced their cytotoxicity in vitro and in vivo. However, there were some limitations to affinity maturation of bsDb by integrating high-affinity Fv mutants, particularly in Fc-fused bsDb with intrinsic high affinity, because of their bivalency. The tetramers fractionated from the bsDb mutant exhibited the highest in vitro growth inhibition among the small bsAbs and was comparable to the in vivo anti-tumor effects of Fc-fused bsDbs. This molecule shows cost-efficient bacterial production and high therapeutic potential. [ABSTRACT FROM AUTHOR]

Aim Human chorionic gonadotropin ( hCG) is used frequently for luteal support in fresh in vitro fertilization cycles as it induces progesterone secretion from the ovaries after oocyte retrieval and modulates the endometrium for implantation in fresh cycles. In contrast, hCG is not usually used for the transfer of cryopreserved-thawed embryos in estrogen/progesterone replacement cycles because ovulation is suppressed. However, several studies have shown that luteinizing hormone and hCG receptors are present in the human endometrium and that hCG can directly induce the decidualization of endometrial stromal cells in vitro. Thus, this study evaluated whether hCG supplementation can be beneficial for cryopreserved-thawed embryo transfer in estrogen/progesterone replacement cycles. Methods One-hundred-and seventy-three cryopreserved-thawed embryo transfer cycles with estrogen/progesterone replacement were divided randomly into two groups. Transdermal oestradiol was used in combination with vaginal progesterone suppositories for HR. The embryo transfer was performed on day 17 and/or day 20 of the HR therapy cycle in both groups. In Group A, 3000 IU of hCG was administered on days 17, 20, and 23. In Group B, hCG was not used. Results There was no significant difference in the average age of the patients, the average number of previous assisted reproductive technology cycles, or the average number of embryo transfers between the two groups. The rates of pregnancy and implantation per embryo were 37.2% and 25.3%, respectively, in Group A and 35.6% and 21.7%, respectively, in Group B. The pregnancy and implantation rates were similar in both groups. Conclusion Supplementation with hCG is not beneficial for cryopreserved-thawed embryo transfer in estrogen/progesterone replacement cycles. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study is to identify the current clinical features of neonatal gastrointestinal perforation in Japan.Methods: A questionnaire about cases of neonatal gastrointestinal perforation treated in recent 5 years was sent to participating institutions of the Japanese Society of Pediatric Surgeons (JSPS).Results: Five hundred and thirty-six neonates with gastrointestinal perforation were treated. They consisted of 42 patients with gastric rupture/perforation (GR), 33 patients with intestinal atresia/stenosis (IA), 3 patients with malrotation (ML), 118 patients with necrotizing enterocolitis (NEC), 160 patients with focal intestinal perforation (FIP), 46 patients with meconium-related ileus (MRI), 77 patients with meconium peritonitis (MP), and 57 patients with other conditions. The total mortality rate was 20.5 %. The mortality rates of the patients with GR, IA, ML, NEC, FIP, MRI, and MP were 9.5, 9.1, 0, 33.1, 20.6, 28.2, and 9.1 %, respectively. In 263 cases involving extremely low-birth-weight neonates (ELBW), 108 died (mortality rate 41.1 %). The mortality rates for ELBW with GR, NEC, FIP, MRI, MP, and other conditions were 27.3 % (3/11), 58.5 % (48/82), 21.6 % (24/111), 70.6 % (24/34), 57.1 % (4/7), and 27.8 % (5/18), respectively.Conclusions: The mortality rates for ELBW decreased from 62.8 % in the previous survey to 41.1 % by the time of this survey. [ABSTRACT FROM AUTHOR]

We identified three nonpeptidic HIV-1 protease inhibitors (PIs), GRL-015, -085, and -097, containing tetrahydropyrano-tetrahydrofuran (Tp-THF) with a C-5 hydroxyl. The three compounds were potent against a wild-type laboratory HIV-1 strain (HIV-1WT), with 50% effective concentrations (EC50s) of 3.0 to 49 nM, and exhibited minimal cytotoxicity, with 50% cytotoxic concentrations (CC50) for GRL-015, -085, and -097 of 80,>100, and>100 µM, respectively. All the three compounds potently inhibited the replication of highly PI-resistant HIV-1 variants selected with each of the currently available PIs and recombinant clinical HIV-1 isolates obtained from patients harboring multidrug-resistant HIV-1 variants (HIVMDR). Importantly, darunavir (DRV) was>1,000 times less active against a highly DRV-resistant HIV-1 variant (HIV-1DRVRP51); the three compounds remained active against HIV- 1DRVRP51 with only a 6.8- to 68-fold reduction. Moreover, the emergence of HIV-1 variants resistant to the three compounds was considerably delayed compared to the case of DRV. In particular, HIV-1 variants resistant to GRL-085 and -097 did not emerge even when two different highly DRV-resistant HIV-1 variants were used as a starting population. In the structural analyses, Tp-THF of GRL-015, -085, and -097 showed strong hydrogen bond interactions with the backbone atoms of active-site amino acid residues (Asp29 and Asp30) of HIV-1 protease. A strong hydrogen bonding formation between the hydroxyl moiety of Tp-THF and a carbonyl oxygen atom of Gly48 was newly identified. The present findings indicate that the three compounds warrant further study as possible therapeutic agents for treating individuals harboring wild-type HIV and/or HIVMDR. [ABSTRACT FROM AUTHOR]

The construction of antibody fragments has the potential to reduce the high cost of therapeutic antibody production, but the structures of these fragments, with monovalency and the lack of an Fc region, can lead to reduced function. Multimerization is one strategy for recovering function that also yields better tumor-to-blood ratios than IgGs or monomeric antibody fragments because of rapid tumor uptake and clearance. Here, we constructed single-chain variable fragment (scFv) multimers by modifying the linker length and domain order of humanized anti- (epidermal growth factor receptor) IgG 528 (h528) and tested their ability to inhibit tumor growth. h528 scFv multimers, expressed using a bacterial expression system, were successfully fractionated and inhibited cancer growth in a multimerization-dependent manner, whereas the h528 scFv monomer showed no inhibition. h528 scFv trimers with variable heavy-light domain order and no linkers showed the highest in vitro and in vivo antitumor effects, which were comparable with those of the approved anti-(epidermal growth factor receptor) therapeutic IgG Cetuximab and Panitumumab. The trimers were also structurally stable in vitro and in vivo, which may be attributable to a strong interaction between the variable heavy and variable light domains of h528 Fv. Thus, h528 scFv multimers, especially trimers, are attractive as the next generation of anti-(epidermal growth factor receptor) therapeutic IgG and offer the possibility of low-cost production. [ABSTRACT FROM AUTHOR]

In an attempt to determine whether mutations in Gag in human immunodeficiency virus type 1 (HIV-1) variants selected with a protease inhibitor (PI) affect the development of resistance to the same or a different PI(s), we generated multiple infectious HIV-1 clones carrying mutated Gag and/or mutated protease proteins that were identified in amprenavir (APV)-selected HIV-1 variants and examined their virological characteristics. In an HIV-1 preparation selected with APV (33 passages, yielding HIVAPVp33), we identified six mutations in protease and six apparently critical mutations at cleavage and non-cleavage sites in Gag. An infectious recombinant clone carrying the six protease mutations but no Gag mutations failed to replicate, indicating that the Gag mutations were required for the replication of HIVAPVp33. An infectious recombinant clone that carried wild-type protease and a set of five Gag mutations (rHIVWTpro12/75/219/390/409gag) replicated comparably to wild-type HIV-1; however, when exposed to APV, rHIVWTpro12/75/219/390/409gag rapidly acquired APV resistance. In contrast, the five Gag mutations significantly delayed the acquisition of HIV-1 resistance to ritonavir and nelfinavir (NFV). Recombinant HIV-1 clones containing NFV resistance-associated mutations, such as D30N and N88S, had increased susceptibilities to APV, suggesting that antiretroviral regimens including both APV and NFV may bring about favorable antiviral efficacy. The present data suggest that the preexistence of certain Gag mutations related to PI resistance can accelerate the emergence of resistance to the PI and delay the acquisition of HIV resistance to other PIs, and these findings should have clinical relevance in the therapy of HIV-1 infection with PI-including regimens. [ABSTRACT FROM AUTHOR]

We identified a novel spirodiketopiperazine (SUP) derivative, AK602/0N04128/GW873140, which specifically blocked the binding of macrophage inflammatory protein lot (MIP-1α) to CCRS with a high affinity (Kd of ≈3 nM), potently blocked human immunodeficiency virus type 1 (HIV-1) gp120/CCRS binding and exerted potent activity against a wide spectrum of laboratory and primary R5 HIV-1 isolates, including multidrug-resistant HIV-1 (H1V-1MDR) (50% inhibitory concentration values of 0.1 to 0.6 nM) in vitro. AK602 competitively blocked the binding to CCR5 expressed on Chinese hamster ovary cells of two monoclonal antibodies, 45523, directed against multidomain epitopes of CCR5, and 45531, specific against the C-terminal half of the second extracellular loop (ECL2B) of CCRS. AK602, despite its much greater anti-H1V-1 activity than other previously published CCRS inhibitors, including TAK-779 and SCH-C, preserved RANTES (regulated on activation normal T-cell expressed and secreted) and MIP-1β binding to CCR5+ their functions, including CC-chemokine-induced chemotaxis and CCR5 internalization, while TAK-779 and SCH-C fully blocked the CC-chemokine/CCRS interactions. Pharmacokinetic studies revealed favorable oral bioavailability in rodents. These data warrant further development of AK602 as a potential therapeutic for HIV-1 infection. [ABSTRACT FROM AUTHOR]

• Nearly half the LH diabody fraction and all the HL fraction were in inactive form. • Diabody fraction components changed dynamically with time. • The association of diabodies corresponded to that of the scFv chimera. • Addition of the deficient HL-R chimera scFV increased cancer cell cytotoxicity. Diabody 31, a bispecific therapeutic antibody, is a heterodimer comprised of two types of chimeric single-chain variable fragments (scFv), that has been identified as a clone with high cytotoxicity against cancer cells. Diabody 31 is inactive as a homodimer and monomer, yet active as a heterodimer in solution. Herein, we examined the association between two kinds of diabodies, LH- and HL type, based on the behavior of four kinds of their constituent chimera scFvs, by size analysis. More than half of the LH diabody fraction, including two types of chimeric scFV that were equally expressed, and nearly all HL diabody fraction components, including one chimeric HL-L scFv, were in inactive form and changed components dynamically as time passed. The association of these diabodies corresponded to that of the scFv chimera, indicating that analysis of these chimeras could predict diabody quality. Furthermore, addition of the deficient HL-R chimera scFv, comprised of an unbalanced chimeric scFv ratio, to the HL diabody fraction increased cancer cell cytotoxicity, with maximal effects obtained upon repeating the process five times. These findings provide insights into the efficient construction of a functional diabody by noting the characteristics of associated diabodies and the molar ratio of expressed chimera scFvs. [ABSTRACT FROM AUTHOR]