Context-dependent role of ATG4B as target for autophagy inhibition in prostate cancer therapy.

ATG4B belongs to the autophagin family of cysteine proteases required for autophagy, an emerging target of cancer therapy. Developing pharmacological ATG4B inhibitors is a very active area of research. However, detailed studies on the role of ATG4B during anticancer therapy are lacking. By analyzing PC-3 and C4-2 prostate cancer cells overexpressing dominant negative ATG4B(C74A)in vitro and in vivo, we show that the effects of ATG4B(C74A) are cell type, treatment, and context-dependent. ATG4B(C74A) expression can either amplify the effects of cytotoxic therapies or contribute to treatment resistance. Thus, the successful clinical application of ATG4B inhibitors will depend on finding predictive markers of response.

Ventilated Infants Have Increased Dead Space and Lower Alveolar Tidal Volumes during the Early versus Recovery Phase of Respiratory Distress.

BACKGROUND: Few studies have reported the measurement of anatomical dead space (Vd,an) and alveolar tidal volume (VA) in ventilated neonates with respiratory distress. OBJECTIVE: The aim of this study was to determine the differences in Vd,an and VA in ventilated infants between the early and recovery phases of respiratory distress using volumetric -capnography (Vcap) based on ventilator graphics and capnograms. METHODS: This study enrolled twenty-five ventilated infants (mean birth weight, 2,220 ± 635 g; mean gestational age, 34.7 ± 3.3 weeks). We adjusted respiratory settings to maintain appropriate oxygenation and tidal volume (VT), and performed Vcap based on waveforms of ventilator graphics and capnograms. Vd,an and VAwere measured in infants with respiratory disorders, immediately after intubation (early phase) and subsequently when they were clinically stable (recovery phase). RESULTS: The early phase, with lower dynamic lung compliance, required a higher level of ventilator support, not positive end-expiratory pressure, than the recovery phase. There were significant differences between the early and recovery phases for Vd,an (mean difference in Vd,an/kg = 0.57 mL/kg; 95% confidence interval [CI], 0.38-0.77; mean difference in Vd,an/VT = 0.10; 95% CI, 0.07-0.14) and VA (mean difference in VA/kg = -0.60 mL/kg; 95% CI, -0.94 to -0.27; mean difference in VA/VT = -0.12; 95% CI, -0.15 to -0.09), despite no difference in VT. CONCLUSIONS: We evaluated changes in Vd,an and VA during mechanical ventilation using Vcap based on waveforms. The increase in Vd,an and decrease in VA suggested dilation of the airways and collapse of the alveoli in ventilated infants with low lung compliance.

De novo X-linked Alport syndrome in a 3-year-old girl.

Alport syndrome (AS) is an inherited kidney disease that may lead to end-stage renal disease in early adult life. It is a clinically and genetically heterogeneous nephropathy. The possibility of a patient with haematuria or proteinuria being diagnosed as having AS cannot be excluded even if the patient is female or if the family history is unknown. We report a 3-year-old girl with a de novo frameshift mutation, c.3906delA p.(Gly1303Aspfs*17), in the COL4A5 gene. The significance of the electron microscopic study on the glomerular basement membrane must be emphasised because it is the first step towards the diagnosis of AS. Genetic analysis provides the only conclusive diagnosis of AS, by determining the mode of inheritance and prognosis.

A pediatric case of hypomagnesemia 1 (HOMG1) caused by novel compound heterozygous mutations in TRPM6.

Hypomagnesemia 1 (HOMG1) is an extremely rare disease with autosomal recessive inheritance that is caused by mutations in the transient receptor potential melastatin 6 gene (TRPM6). Here, we describe a pediatric HOMG1 case with novel compound heterozygous mutations of TRPM6 (c.1483 C > T [p.Gln495*] and c.2715del [p.Trp905*]) in a 2-month-old boy who developed refractory seizures due to hypomagnesemia with secondary hypocalcemia.

Clinical significance and pathogenic function of connective tissue growth factor (CTGF/CCN2) in osteolytic mandibular squamous cell carcinoma.

BACKGROUND: Mandibular bone destruction is a frequent occurrence in oral squamous cell carcinoma. However, the relationship between the bone destruction and associated factors is unclear. Here, the role and diagnostic utility of connective tissue growth factor (CCN2) in bone destruction of the mandible was investigated. PATIENTS AND METHODS: The production of CCN2 was explored by using immunohistochemistry on paraffin-embedded tissues from 20 cases of mandibular squamous cell carcinoma. The effect of CCN2 on osteoclastogenesis was examined in vitro by using total bone marrow cell populations from male mice. RESULTS: Immunohistochemical analysis showed that CCN2-positive signals were closely associated with destructive invasion of the mandible by oral squamous cell carcinomas. Consistent with these results, recombinant human CCN2 (rCCN2) stimulated tartrate-resistant acid phosphatase (TRAP)-positive osteoclast-like cell formation in vitro. CONCLUSION: CCN2 can be considered a diagnostic marker and target for treatment in oral osteolytic mandibular squamous cell carcinoma.

Bone destruction by invading oral squamous carcinoma cells mediated by the transforming growth factor-beta signalling pathway.

BACKGROUND: Gingival squamous cell carcinoma (SCC) cells frequently invade mandibular bone, and this destruction is associated with a worse prognosis. However, the relationship between bone destruction and associated factors is unclear. In this study, the role and diagnostic utility of transforming growth factor-beta (TGF-beta) type I receptor (TbetaRI) in bone destruction of the mandible was investigated. PATIENTS AND METHODS: The expression of TbetaRI was explored by using an immunohistochemical method on paraffin-embedded tissues from 21 cases of mandibular SCC. An inhibitor of the kinase activity of the TbetaRI (TbetaRI-I) was used to assess the role of TbetaRI in bone destruction by a human oral SCC cell line (HSC-2) that highly expresses TbetaRI. RESULTS: TbetaRI-positive signals were closely associated with destructive invasion of the mandible by oral SCC cells. Consistent with these results, TbetaRI-I greatly reduced HSC-2 cell-induced bone destruction and osteoclast formation in vivo and in vitro. TbetaRI-I treatment reduced the expression of TNF-alpha, RANKL and connective tissue growth factor (CTGF/CCN2), all of which were up-regulated by TGF-beta in HSC-2 cells. CONCLUSION: These data demonstrated an important role for TGF-beta signalling in bone invasion by oral SCC cells, and suggest that the bone destruction is mediated by RANKL, TNF-alpha and CCN2.