CD40-mediated immune cell activation enhances response to anti-PD-1 in murine intrahepatic cholangiocarcinoma

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Frequency of O6‐methylguanine‐DNA methyltransferase promoter methylation in cytological samples from small cell lung cancer

Background. In a phase II study for patients with relapsed small cell lung cancer (SCLC), the administration of Temozolomide, an alkylating agent used in gliomas and anaplastic astrocytoma, showed a effective activity when O⁶‐methylguanine‐DNA methyltransferase (MGMT) gene promoter was methylated. Methods. We tested the feasibility of MGMT promoter status evaluation in small biopsies and cytological specimens routinely processed for diagnostic purposes. We tested samples from 56 patients with SCLC: 30 tissue biopsies, 17 fine‐needle aspiration biopsy, 8 bronchial washing, and 1 was a sputum. Biopsies and fine‐needle aspiration biopsy were fixed in formalin, bronchial washing and sputum in Dubosq Brazil. DNA was extracted after macrodissection of the areas containing the maximum number of cancer cells. MGMT promoter methylation status was assessed by methylation specific PCR. Results. Methylation analysis was obtained in 54 samples (54/56) and failed in two bronchial wash. MGMT promoter was methylated in 35.2% of the cases without any significant difference between histological and cytological samples (37.9% vs. 32%). Conclusion. MGMT promoter methylation is present in SCLC and cytological samples are perfectly adequate for methylation analysis, even if they were taken during routine diagnostic procedures, using different fixative and with low number and percentage of cancer cells. Diagn. Cytopathol. 2015;43:947–952. © 2015 Wiley Periodicals, Inc.     

Effect of Orthognathic Surgery on the Posterior Airway Space in Patients Affected by Skeletal Class III Malocclusion

Introduction

Dentofacial deformity refers to deviations from normal facial proportions and dental relationships that are severe enough to be handicapping. These anomalies involve many aspects of patient’s life and are sometimes also associated with a reduction of pharyngeal air space. Through orthognathic surgery it is possible to treat dentofacial deformities: this kind of surgery has several effects on skeletal structures and it has changes, as it is demonstrated by many studies, also on the upper airways. The orthognathic surgeries commonly used to correct this deformity are the mandibular setback and the maxillary advancement procedures. This study aims to evaluate the effects of maxillary and mandibular surgery on pharyngeal airway dimensions in skeletal class III malocclusions.

Materials and methods

This study considers 76 patients, treated between 2007 and 2013 by maxillary advancement (11 patients), maxillary advancement and mandibular setback (39 patients), maxillary advancement, mandibular setback and genioplasty reduction (26 patients). Cranial latero-lateral radiography was used to compare oropharyngeal airway morphologies before and 1 year after surgery.

Conclusion

The surgeon should consider bimaxillary surgery rather than mandibular setback surgery to correct a class III deformity to prevent the development of obstructive sleep apnea syndrome; in fact, bimaxillary surgery might have less effect on reduction of the pharyngeal airway than mandibular setback surgery only.     

Transgene-mediated cosuppression and RNA interference enhance germ-line apoptosis in Caenorhabditis elegans

Introduction of multiple copies of a germ-line-expressed gene elicits silencing of the corresponding endogenous gene during Caenorhabditis elegans oogenesis; this process is referred to as germ-line cosuppression. Transformed plasmids assemble into extrachromosomal arrays resembling extra minichromosomes with repetitive structures. Loss of the transgene extrachromosomal array leads to reversion of the silencing phenomenon. Cosuppression and RNAi depend upon some of the same genes. In the C. elegans germ line, about half the cells undergo a physiological programmed cell death that shares most genetic requirements with somatic apoptosis. In addition, apoptosis is stimulated by DNA damage and synaptic failure mediated through different apoptotic checkpoints. We found that both germ-line cosuppression and RNAi of germ-line-expressed genes enhance apoptosis during C. elegans oogenesis. In contrast, apoptosis is not enhanced by extrachromosomal arrays carrying genes not driven by germ-line-specific promoters that thus do not elicit transgene-mediated cosuppression/silencing. Similarly, introduction of doubled-stranded RNA that shares no homology with endogenous genes has no effect on apoptosis. "Silencing-induced apoptosis" is dependent upon sir-2.1 and cep-1 (the worm p53 ortholog), and is accompanied by a rise in RAD-51 foci, a marker for ongoing DNA repair, indicating induction of DNA double-strand breaks. This finding suggests that the DNA damage-response pathway is involved. RNAi and cosuppression have been postulated as defense mechanisms against genomic intruders. We speculate that the mechanism here described may trigger the elimination of germ cells that have undergone viral infection or transposon activation.