Peroxisome proliferator-activated receptor-γ signalling protects hair follicle stem cells from chemotherapy-induced apoptosis and epithelial-mesenchymal transition.

BACKGROUND: Permanent chemotherapy-induced alopecia (pCIA), for which preventive interventions remain limited, can manifest with scarring. While the underlying pathomechanisms of pCIA are unclear, depletion of epithelial hair follicle (HF) stem cells (eHFSCs) is likely to play a role. OBJECTIVES: To explore the hypothesis that, besides apoptosis, eHFSCs undergo pathological epithelial-mesenchymal transition (EMT) in pCIA, thus explaining the scarring phenotype. Furthermore, we tested whether a peroxisome proliferator-activated receptor (PPAR)-γ modulator could prevent pCIA-associated pathomechanisms. METHODS: Organ-cultured human scalp HFs were treated with the cyclophosphamide metabolite 4-hydroperoxycyclophosphamide (4-HC). Additionally, HFs were pretreated with the agonistic PPAR-γ modulator N-acetyl-GED-0507-34-Levo (NAGED), which has previously been shown to promote K15 expression and antagonize EMT in eHFSCs. RESULTS: In accordance with anticipated hair bulb cytotoxicity, dystrophy and catagen induction, 4-HC promoted apoptosis along with increased p53 expression, DNA damage and pathological EMT in keratin 15+ (K15) eHFSCs, as evidenced by decreased E-cadherin expression and the appearance of fibronectin+ and vimentin+ cells in the hair bulge. Pretreatment with NAGED protected against 4-HC-induced hair bulb cytotoxicity/dystrophy, and apoptosis, p53 upregulation and EMT in the bulge, thereby significantly preventing depletion of K15+ human eHFSCs ex vivo. CONCLUSIONS: Since a key cyclophosphamide metabolite alone suffices to damage and deplete human scalp eHFSCs by promoting apoptosis, DNA damage and EMT ex vivo, strategies to prevent pCIA need to target these pathomechanisms. Given the ability of NAGED to prevent chemotherapy-induced eHFSCs damage ex vivo, our study introduces the stimulation of PPAR-γ signalling as a novel intervention strategy for the prevention of pCIA.

Minimally invasive closed-chest ultrasound-guided substance delivery into the pericardial space in mice.

Organ-directed gene transfer remains an attractive method for both gaining a better understanding of heart disease and for cardiac therapy. However, virally mediated transfer of gene products into cardiac cells requires prolonged exposure of the myocardium to the viral substrate. Pericardial injection of viral vectors has been proposed and used with some success to achieve myocardial transfection and may be a suitable approach for transfection of atrial myocardium. Indeed, such an organ-specific method would be particularly useful to reverse phenotypes in young and adult genetically altered murine models of cardiac disease. We therefore sought to develop a minimally invasive technique for pericardial injection of substances in mice. Pericardial access in anaesthetised, spontaneously breathing mice was achieved using continuous high-resolution ultrasound guidance. We could demonstrate adequate delivery of injected substances into the murine pericardium. Atrial epicardial and myocardial cells were transfected in approximately one third of mice injected with enhanced green fluorescent protein-expressing adenovirus. Cellular expression rates within individual murine atria were limited to a maximum of 20 %; therefore, expression efficiency needs to be further improved. Minimally invasive, ultrasound-guided injection of viral material appears a technically challenging yet feasible method for selective transfection of atrial epi- and myocardium. This pericardial injection method may be useful in the evaluation of potential genetic interventions aimed at rescuing atrial phenotypes in transgenic mouse models.

Human genome dispersal and evolution of 4q35 duplications and interspersed LSau repeats.

We have investigated the evolutionary history of the 4q35 paralogous region, and of a sub-family of interspersed LSau repeats. In HSA, 4q35 duplications were localized at 1q12, 3p12.3, 4q35, 10q26, 20cen, whereas duplicons and interspersed LSau repeats simultaneously labeled the p arm of acrocentric chromosomes. A multi-site localization of 4q35-like sequences was also observed in PTR, GGO, PPY, HLA (Hominoidea) and PAN (Old World monkey), thus indicating that duplications of this region have occurred extensively in the two clades, which diverged at least 25 million years ago. In HSA, PTR and PAN, 4q35-derived duplicons co-localized with rDNA, whereas in GGO and PPY this association was partially lacking. In PAN, the single- and multi-site distribution of rDNA and paralogous sequences, respectively, indicates a different timing of sequence dispersal. The sub-family of interspersed LSau repeats showed a lesser dispersal than 4q35 duplications both in man and great apes. This finding suggests that duplications and repeated sequences have undergone different expansion/contraction events during evolution. The mechanisms underlying the dispersal of paralogous regions may be further derived through studies comparing the detailed structural organization of these genomic regions in man and primates.

The structure of duplications on human acrocentric chromosome short arms derived by the analysis of 15p.

We report the molecular analysis of a 130-kb DNA region containing a junction between beta and non-beta satellite DNA from chromosome 15p. The genomic region is characterized by beta satellite blocks intermingled with variants of the D4Z4 repeat, and duplicons from 4q24 and 4q35. Besides the p-arm of acrocentric chromosomes, the duplicons showed a wide genomespread involving pericentromeric, sub-telomeric, and interstitial regions. In this regard, the paralogous sequences were characterized by a high similarity index (96%), thus indicating a recent transposition during the evolution. The acrocentrics differedwith regard to the location of the 4q24 paralogous region, since it mapped on the p-arm of chromosomes 13-15 and 21, but only on 22q11.2. Conversely, the 4q35 duplication marked the p-arm of all the acrocentrics. In different individuals, the short arm of acrocentric chromosomes revealed a great variability of sequence representation and location at p11 and/or p13 for both the 4q24 and 4q35 duplications. The studied genomic region from chromosome 15p, of which a contig of approximately 200 kb has been derived, could lead to more detailed investigations into the sequence organization and possible biological function of chromosome regions that are located close to the rDNA array.

[Intestinal anastomosis with biodegradable ring]. / Anastomosi intestinali mediante anello bioframmentabile (BAR).

The authors report their experience using biofragmentable anastomosis ring (BAR) in bowel anastomosis. Starting January 1993 to February 1994, 46 intestinal anastomoses were performed using BAR, and particularly 39 end-to-end colo-colostomies, 2 end-to-side colo-colostomies and 5 end-to-side ileo-colostomies. 35 patients were affected by colonic neoplasm, 5 patients by diverticular colonic complications- and 5 patients by several unusual bowel diseases. Four emergency operations were performed, while 42 patients had an accurate bowel preparation before surgery. In this series of patients one case of preoperative mortality is reported, due to massive pulmonary embolism. Instead several minor complications occurred in other patients, such as paroxysmal atrial fibrillation (one case), basal pleuritis (one case), hyperpyrexia (three cases), temporary subocclusion or delayed canalization (five cases). Only one patient suffered from intestinal occlusion induced by adhesions and a second laparotomy was required. Delayed canalization seems to be caused by the small size of the BAR employed (25 mm) or by inadequate intestinal preparation, that usually occurs in emergency operations. After surgery all patients were followed up and 18 of them were examined by coloscopy six months after surgery. No clinical problem connected with bowel anastomosis was reported and all anastomosis looked quite previous and resilient. No anastomotic stenosis was found. In our experience and from recent reviewed reports, BAR seems to be a rapid, effective and safe device for sutureless bowel anastomosis.

[Role of surgery in the treatment of acute hemorrhagic non-variceal lesions in the upper gastrointestinal tract]. / Ruolo della chirurgia nel trattamento delle lesioni emorragiche acute non varicose del tratto gastro-intestinale superiore.

From January 1993 to December 1994, out of 244 cases of upper gastrointestinal hemorrhage observed 25 patients underwent surgical treatment. Twenty-nine bleeding varices were excluded from this study. Early endoscopy revealed the source of bleeding almost in all cases (84%). All patients received, at the time of admission, medical treatment associated in 7 cases (28%) to endoscopic injection therapy. Emergency surgery indications were massive bleeding persistent bleeding, rebleeding and macroscopic findings of lesions. The aim of this report is to verify the respective roles of medical, endoscopic and surgical therapies in relation to the nature of the bleeding lesion and the entity of the hemorrhage. Results with regard to indication, clinical data, surgical technique were compared with literature data.

[Thyroid carcinoma in hyperthyroid syndromes]. / Il carcinoma tiroideo nelle sindromi ipertiroidee.

The relationship between hyperthyroidism and carcinoma of the thyroid is still uncertain. The incidence of thyroid carcinoma ranges from 0.3 to 16.6%. Between 1984 and 1994 the Authors observed 9 patients affected with thyroid cancer and toxic nodular goiter (4 patients) or Basedow disease (2 patients) or scintigraphic evidence of single hyperfunctioning nodule (3 patients). Six out of the 9 cases were diagnosed as papillary cancer, while three as follicular cancer. A carcinoma was diagnosed before operation in only one case, while in the other 8 patients, the diagnosis was obtained by histological examination of the specimen. Four patients underwent subtotal thyroidectomy, while five patients underwent radical lobectomy. All patients are alive and in good health; the average follow-up was 48 months.

[Eosinophilic gastritis. Clinico-pathologic considerations on a case and review of the literature]. / Gastrite eosinofila. Considerazioni clinico-patologiche su di un caso e revisione della letteratura.

The clinical, radiographic and histological features of a case of eosinophilic gastritis in a 26 year old-man without personal or familial signs of allergy are reported. The Authors pointed out the importance of radiographic and histological aspects of the case studied. Therefore they represent essential methods for a correct diagnosis and an appropriate management that in this case is only pharmacological. The diagnosis of eosinophilic gastritis is, however, important for the recognition of specific allergens.

Carcinoma of the gastric stump following partial gastrectomy (Billroth II operation) for benign gastroduodenal lesions. Preliminary results.

A series of 110 patients out of 2,200, who had undergone Billroth II partial gastrectomy for benign lesions, between 1945 and 1980, was reviewed in order to perform clinical, biochemical and endoscopical examinations. In this group 9 patients (8.18%) showed gastric stump cancer and in 4 (3.63%) esophageal cancer was detected. The average time interval between previous operation and carcinoma diagnosis was of 28 years and 6 months. Eight patients out of 9 were males aging from 47 to 82, while the only woman was 65 (overall average: 63). The stump cancer presents at the same age and gives the same symptoms as primitive gastric carcinoma, but with worse results and prognosis. After having underlined some pathogenetic problems, the Authors show personal results and confirm the utility of an accurate endoscopical and clinical follow up especially for patients operated on since more than twenty years.