The hematopoietic cell-specific Rho GTPase inhibitor ARHGDIB/D4GDI limits HIV type 1 replication

Rho GTPases are able to influence the replication of human immunodeficiency virus type 1 (HIV-1). However, little is known about the regulation of HIV-1 replication by guanine nucleotide dissociation inhibitors (GDIs), one of the three major regulators of the Rho GTPase activation cycle. From a T cell-based cDNA library screening, ARHGDIB/RhoGDIβ, a hematopoietic lineage-specific GDI family protein, was identified as a negative regulator of HIV-1 replication. Up-regulation of ARHGDIB attenuated the replication of HIV-1 in multiple T cell lines. The results showed that (1) a significant portion of RhoA and Rac1, but not Cdc42, exists in the GTP-bound active form under steady-state conditions, (2) ectopic ARHGDIB expression reduced the F-actin content and the active forms of both RhoA and Rac1, and (3) HIV-1 infection was attenuated by either ectopic expression of ARHGDIB or inhibition of the RhoA signal cascade at the HIV-1 Env-dependent early phase of the viral life cycle. This is in good agreement with the previous finding that RhoA and Rac1 promote HIV-1 entry by increasing the efficiency of receptor clustering and virus-cell membrane fusion. In conclusion, the ARHGDIB is a lymphoid-specific intrinsic negative regulator of HIV-1 replication that acts by simultaneously inhibiting RhoA and Rac1 functions.     

Association between genetic variations in surfactant protein d and emphysema, interstitial pneumonia, and lung cancer in a Japanese population

Surfactant protein D (SFTPD) is a lung-specific anti-inflammatory factor that antagonizes inflammation by inhibiting oxidative stress and stimulating innate immunity. Variations in SFTPA2 and SFTPB, genes for other surfactant proteins, have been associated with lung cancer. We therefore investigated associations between SFTPD variations and lung cancer as well as emphysema and interstitial pneumonia, which are characterized by chronic inflammation from which lung cancer often arises. DNA from 1342 autopsy samples, including those from 140 subjects with lung cancer, was investigated. The single nucleotide polymorphism (SNP) rs721917, which results in methionine being exchanged for threonine at amino acid 11 (the Met11Thr variation), tended to be associated with emphysema and was associated with interstitial pneumonia and lung cancer. A haplotype analysis revealed that the haplotypes associated with emphysema and lung cancer differed from that associated with interstitial pneumonia, suggesting a differential role for SFTPD in the development of these diseases. A mediating analysis did not reveal a mediating effect exerted by emphysema or interstitial pneumonia on lung cancer. Our results suggested that SFTPD plays a role in the development of lung cancer and that the role for lung cancer may differ from that for interstitial pneumonia.     

Contraindications and image-defined risk factors in laparoscopic resection of abdominal neuroblastoma

Purpose

Minimally invasive surgery (MIS) has become widely accepted as a technique for abdominal neuroblastoma resection. However, the indications for MIS are still controversial. The aim of this study was to evaluate image-defined risk factors (IDRFs), complications, and oncologic outcomes in patients with abdominal neuroblastomas treated with MIS.

Methods

Between August 1998 and February 2016, MIS was planned for 20 children with abdominal neuroblastomas. Clinical data were retrospectively reviewed and compared between the IDRF-negative and IDRF-positive patients.

Results

On the basis of the latest IDRF guidelines, five patients were classified as IDRF-positive and four of them had operative complications; namely, partial infarction of the ipsilateral kidney or open conversion. Concerning the two patients who needed open conversion, the primary reason for open conversion was difficulty in dissection of the tumor from the vena cava. Preoperative images of these cases showed either deformation or subtotal encasement of the vena cava. Relapse occurred in three high-risk patients and in none of the low/intermediate-risk patients. No complication occurred in the IDRF-negative cases.

Conclusions

IDRF-negative might be a good indication for MIS for abdominal neuroblastoma. However, deformation or subtotal encasement of the vena cava should be considered as IDRF-positive for MIS.

     

Effects of retrieving context information on accuracy-confidence relationships in recognition memory for faces

We investigated how retrieval conditions affect accuracy-confidence (A-C) relationship sin recognition memory for faces. Seventy participants took a face-recognition test and rated their confidence in their judgment. Twenty-three participants were assigned to a retrieval condition, where they were encouraged to remember background information (scenery) of each picture just before rating their confidence. Twenty-four participants were assigned to a verbalizing condition, in which they were encouraged to remember and verbally describe the background of each picture before rating. Twenty-three participants were assigned to a control condition. The results showed that for the control condition, an A-C relationship was found for old items but not for new items, replicating the results of Takahashi (1998) and Wagenaar (1988). In contrast, in the retrieval condition, an A-C relationship was found for both old and new items. In the verbalizing condition, an A-C relationship was not found for either old or new items. The results showed that retrieving background information affects A-C relationships, supporting the idea that confidence ratings rely not only on memory traces but also on various kinds of information such as retrieved background scenery. Implications for eyewitness testimony were discussed.     

Malignant solitary fibrous tumor of the soft tissue: a cytogenetic study

We report on a case of a solitary fibrous tumor that developed in the thigh of an 82-year-old woman. The tumor was composed of areas of high-grade sarcoma and typical solitary fibrous tumor. Its karyotype was: 70,XXX,+X[4],+1[2],add(1)(p36)[4],add(1)[2],+2[4],-3[4],+6[4],add(6)(p11)x2[4],+7[4],+9[3],-11[4],-12[4],-13[4],add(13)(p11)x2[4],-14[4],+15[4],-16[3],-17[4],-19[4],+20,[4],+21[4],+22[2],+mar1x2[4][cp4].     

Human plasma metabolic profiles of benzydamine,a flavin-containing monooxygenase probe substrate,simulated with pharmacokinetic data from control and humanized-liver mice

1.?Benzydamine is used clinically as a nonsteroidal anti-inflammatory drug in oral rinses and is employed in preclinical research as a flavin-containing monooxygenase (FMO) probe substrate. In this study, plasma concentrations of benzydamine and its primary N-oxide and N-demethylated metabolites were investigated in control TK-NOG mice, in humanized-liver mice, and in mice whose liver cells had been ablated with ganciclovir.

2.?Following oral administration of benzydamine (10?mg/kg) in humanized-liver TK-NOG mice, plasma concentrations of benzydamine N-oxide were slightly higher than those of demethyl benzydamine. In contrast, in control and ganciclovir-treated TK-NOG mice, concentrations of demethyl benzydamine were slightly higher than those of benzydamine N-oxide.

3.?Simulations of human plasma concentrations of benzydamine and its N-oxide were achieved using simplified physiologically based pharmacokinetic models based on data from control TK-NOG mice and from reported benzydamine concentrations after low-dose administration in humans. Estimated clearance rates based on data from humanized-liver and ganciclovir-treated TK-NOG mice were two orders magnitude high.

4.?The pharmacokinetic profiles of benzydamine were different for control and humanized-liver TK-NOG mice. Humanized-liver mice are generally accepted human models; however, drug oxidation in mouse kidney might need to be considered when probe substrates undergo FMO-dependent drug oxidation in mouse liver and kidney.