Protection of Macaques with Diverse MHC Genotypes against a Heterologous SIV by Vaccination with a Deglycosylated Live-Attenuated SIV

HIV vaccine development has been hampered by issues such as undefined correlates of protection and extensive diversity of HIV. We addressed these issues using a previously established SIV-macaque model in which SIV mutants with deletions of multiple gp120 N-glycans function as potent live attenuated vaccines to induce near-sterile immunity against the parental pathogenic SIVmac239. In this study, we investigated the protective efficacy of these mutants against a highly pathogenic heterologous SIVsmE543-3 delivered intravenously to rhesus macaques with diverse MHC genotypes. All 11 vaccinated macaques contained the acute-phase infection with blood viral loads below the level of detection between 4 and 10 weeks postchallenge (pc), following a transient but marginal peak of viral replication at 2 weeks in only half of the challenged animals. In the chronic phase, seven vaccinees contained viral replication for over 80 weeks pc, while four did not. Neutralizing antibodies against challenge virus were not detected. Although overall levels of SIV specific T cell responses did not correlate with containment of acute and chronic viral replication, a critical role of cellular responses in the containment of viral replication was suggested. Emergence of viruses with altered fitness due to recombination between the vaccine and challenge viruses and increased gp120 glycosylation was linked to the failure to control SIV. These results demonstrate the induction of effective protective immune responses in a significant number of animals against heterologous virus by infection with deglycosylated attenuated SIV mutants in macaques with highly diverse MHC background. These findings suggest that broad HIV cross clade protection is possible, even in hosts with diverse genetic backgrounds. In summary, results of this study indicate that deglycosylated live-attenuated vaccines may provide a platform for the elucidation of correlates of protection needed for a successful HIV vaccine against diverse isolates

Prenatal Diagnosis of Isolated Agnathia-Otocephaly: A Case Report and Review of the Literature

Agnathia is a rare disease characterized by the absence of a mandible. Few cases of prenatally diagnosed isolated agnathia have been reported. We present a case report and review of the literature of prenatally diagnosed agnathia. A 38-year-old woman (gravida 0, para 0) was referred to our hospital at 28 weeks and 3 days of gestation for fetal evaluation because of polyhydramnios and suspected facial anomalies. Three-dimensional ultrasonography and MRI indicated agnathia. Premature rupture of the membranes occurred before the parents could reach a decision on the postnatal treatment. We performed emergency cesarean section on the second day of the 33rd week of gestation. The neonate was deemed nonresuscitable and he died of airway obstruction shortly after birth. Because agnathia is associated with very poor prognosis, accurate prenatal diagnosis and detailed counseling should be promptly provided before unexpected delivery to the parents for the determination of postnatal treatment

Mutations in the Mitochondrial ND1 Gene Are Associated with Postoperative Prognosis of Localized Renal Cell Carcinoma

We analyzed mutations in the mitochondrial ND1 gene to determine their association with clinicopathological parameters and postoperative recurrence of renal cell carcinoma (RCC) in Japanese patients. Among 62 RCC cases for which tumor pathology was confirmed by histopathology, ND1 sequencing revealed the presence of 30 mutation sites in 19 cases. Most mutations were heteroplasmic, with 16 of 19 cases harboring one or more heteroplasmic sites. Additionally, 12 sites had amino acid mutations, which were frequent in 10 of the cases. The 5-year recurrence-free survival (RFS) rate was significantly worse in patients with tumors >40 mm in diameter (p = 0.0091), pathological T (pT) stage ≥3 (p = 0.0122), Fuhrman nuclear atypia grade ≥III (p = 0.0070), and ND1 mutations (p = 0.0006). Multivariate analysis using these factors revealed that mutations in ND1 were significantly associated with the 5-year RFS rate (p = 0.0044). These results suggest a strong correlation between the presence of ND1 mutations in cancer tissue and postoperative recurrence of localized RCC in Japanese patients

D-loop Mutations in Renal Cell Carcinoma Improve Predictive Accuracy for Cancer-Related Death by Integrating with Mutations in the NADH Dehydrogenase Subunit 1 Gene

Renal cell carcinoma (RCC) is associated with various genetic alterations. Although whole-genome/exome sequencing analysis has revealed that nuclear genome alterations are associated with clinical outcomes, the association between nucleotide alterations in the mitochondrial genome and RCC clinical outcomes remains unclear. In this study, we analyzed somatic mutations in the mitochondrial D-loop region, using RCC samples from 61 consecutive patients with localized RCC. Moreover, we analyzed the relationship between D-loop mutations and NADH dehydrogenase subunit 1 (MT-ND1) mutations, which we previously found to be associated with clinical outcomes in localized RCC. Among the 61 localized RCCs, 34 patients (55.7%) had at least one mitochondrial D-loop mutation. The number of D-loop mutations was associated with larger tumor diameter (>32 mm) and higher nuclear grade (≥ISUP grade 3). Moreover, patients with D-loop mutations showed no differences in cancer-specific survival when compared with patients without D-loop mutations. However, the co-occurrence of D-loop and MT-ND1 mutations improved the predictive accuracy of cancer-related deaths among our cohort, increasing the concordance index (C-index) from 0.757 to 0.810. Thus, we found that D-loop mutations are associated with adverse pathological features in localized RCC and may improve predictive accuracy for cancer-specific deaths when combined with MT-ND1 mutations

Electron-Deficient Pt₂M₂Pt₂ Hexanuclear Metal Strings (M = Pt, Pd) Supported by Triphosphine Ligands

Electron-deficient Pt₂M₂Pt₂ hexanuclear clusters, [Pt₄M₂(μ-dpmp)₄(XylNC)₂]­(PF₆)₄ (M = Pt (<b>7</b>), Pd (<b>8</b>); dpmp = bis­((diphenylphosphino)­methyl)­phenylphosphine), were synthesized by oxidation of hydride-bridged hexanuclear clusters [Pt₄M₂(μ-H)­(μ-dpmp)₄(XylNC)₂]­(PF₆)₃ (M = Pt (<b>2</b>), Pd (<b>3</b>)) and were revealed to involve a linearly ordered Pt₂M₂Pt₂ array joined by delocalized bonding interactions with 84 cluster valence electrons, which are discussed on the basis of DFT calculations. The central M–M distances of <b>7</b> and <b>8</b> are significantly reduced upon the apparent loss of a hydride unit from the M–H–M central part of <b>2</b> and <b>3</b>, indicating that the bonding electrons in the adjacent M–Pt bonds migrate into the central M–M bond to result in a dynamic structural change during two-electron oxidation of the hexanuclear metal strings. A similar Pt₆ complex terminated by two iodide anions, [Pt₆I₂(μ-dpmp)₄]­(PF₆)₂ (<b>9</b>), was synthesized from [Pt₆(μ-H)­I₂(μ-dpmp)₄]­(PF₆) (<b>5</b>) by treatment with [Cp₂Fe]­[PF₆]. Complexes <b>7</b> and <b>8</b> were readily reacted with the neutral two-electron donors XylNC, CO, and phosphines to afford the trinuclear complexes [Pt₂M­(μ-dpmp)₂(XylNC)­L]­(PF₆)₂ (M = Pt, L = XylNC (<b>1a</b>), CO (<b>10</b>), PPh₃ (<b>11</b>); M = Pd, L = XylNC (<b>1b</b>)) through cleavage of the electron-deficient central M–M bond. When complex <b>7</b> was reacted with the diphosphines (<b>PP</b>) <i>trans</i>-Ph₂PCHCHPPh₂ (dppen) and Ph₂P­(CH₂)₂PPh₂ (dppe), the diphosphine was inserted into the central M–M bond to afford [(XylNC)­Pt₃(μ-dpmp)₂(<b>PP</b>)­Pt₃(μ-dpmp)₂(XylNC)]­(PF₆)₄ (<b>12</b>), which was transformed by treatment with another 1 equiv of diphosphine into the asymmetric trinuclear complexes [Pt₃(μ-dpmp)₂(XylNC)­(<b>PP</b>)]­(PF₆)₂ (<b>13</b>). A further ligand exchange reaction of <b>13a</b> (<b>PP</b> = <i>trans</i>-dppen) provided the diphosphine-terminated symmetrical Pt₃ complex [Pt₃(μ-dpmp)₂(L)₂]­(PF₆)₂ (L = <i>trans</i>-dppen (<b>14a</b>)). Complexes <b>7</b> and <b>8</b> were also reacted with [AuCl­(PPh₃)] to yield the Pt₂MAu heterotetranuclear complexes [Pt₂MAuCl­(μ-dpmp)₂(PPh₃)­(XylNC)]­(PF₆)₂ (M = Pt (<b>15</b>), Pd (<b>16</b>)), in which the Pt₂M trinuclear fragment is inserted into the Au–Cl bond in a 1,1-fashion on the central M atoms of the Pt₂M₂Pt₂ string