Publications by authors named "Monica Cricca"

35 Publications

Epidemiologic case investigation on the zoonotic transmission of Staphylococcus aureus infection from goat to veterinarians.

Zoonoses Public Health 2021 May 5. Epub 2021 May 5.

Department of Veterinary Medical Sciences, University of Bologna, Bologna, Italy.

Staphylococcus aureus infection led to a case of goat abortion, and four veterinarians contracted S. aureus infection from the goat during and after the abortion. Three veterinarians assisted a doe during the dystocic delivery of a dead foetus. Seventy-two hours after the dystocia, which ended with the goat's death, the veterinarians who assisted during the kidding and the veterinarian who performed the necropsy showed the presence of multiple, isolated, painful pustules 1-5 mm in diameter located along their forearms and knees. S. aureus was isolated from the pustules of the veterinarians, the placenta and uterus of the goat, the organs (brain, thymus gland, abomasum, liver and spleen) of the foetus, the scrotum and eye swabs of the buck, and mammary pustules of another goat from the same herd. Histological analysis revealed purulent metritis and inflammation of the placental cotyledons. Additional investigations eliminated the chances of other infections. S. aureus isolates recovered from the veterinarians, goats, foetus and buck were sensitive to the tested anti-microbials and did not encode staphylococcal enterotoxin genes (sea, ser, sep, see, seg and sei). The isolates were closely related, as indicated by the results of Fourier-transform infrared spectroscopy and comparative whole-genome sequencing analysis. The results of this study clearly support the hypothesis that an episode of professional zoonosis was caused by S. aureus infection during the abortion and also highlight the need for bacterial subtyping in epidemiological surveys.
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http://dx.doi.org/10.1111/zph.12836DOI Listing
May 2021

Breakthrough invasive fungal infection after liver transplantation in patients on targeted antifungal prophylaxis: A prospective multicentre study.

Transpl Infect Dis 2021 Mar 26:e13608. Epub 2021 Mar 26.

Division of Infectious Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.

Objective: To investigate the rate of and the risk factors for breakthrough-IFI (b-IFI) after orthotopic liver transplantation (OLT) according to the new definition proposed by Mycoses-Study-Group-Education-and-Research-Consortium (MSG-ERC) and the European-Confederation-of-Medical-Mycology (ECMM).

Methods: Multicenter prospective study of adult patients who underwent OLT at three Italian hospitals, from January 2015 to December 2018. Targeted antifungal prophylaxis (TAP) protocol was developed and shared among participating centers. Follow-up was 1-year after OLT. B-IFI was defined as infection occurring during exposure to antifungal prophylaxis. Risk factors for b-IFI were analyzed among patients exposed to prophylaxis by univariable analysis.

Results: We enrolled 485 OLT patients. Overall compliance to TAP protocol was 64.3%, 220 patients received antifungal prophylaxis, 172 according to TAP protocol. Twenty-nine patients were diagnosed of IFI within 1 year after OLT. Of them, 11 presented with b-IFI within 17 (IQR 11-33) and 16 (IQR 4-30) days from OLT and from antifungal onset, respectively. Then out of 11 patients with b-IFI were classified as having high risk of IFI and were receiving anti-mould prophylaxis, nine with echinocandins and one with polyenes. Comparison of patients with and without b-IFI showed significant differences for prior Candida colonization, need of renal replacement therapy after OLT, re-operation, and CMV infection (whole blood CMV-DNA >100 000 copies/mL). Although non-significant, a higher rate of b-IFI in patients on echinocandins was observed (8.2% vs 1.8%, P = .06).

Conclusions: We observed 5% of b-IFI among OLT patients exposed to antifungal prophylaxis. The impact of echinocandins on b-IFI risk in this setting should be further explored.
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http://dx.doi.org/10.1111/tid.13608DOI Listing
March 2021

Metabolic profiling of Candida clinical isolates of different species and infection sources.

Sci Rep 2020 10 7;10(1):16716. Epub 2020 Oct 7.

Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, Bologna, Italy.

Candida species are the most common cause of opportunistic fungal infections. Rapid identification and novel approaches for the characterization of these fungi are of great interest to improve the diagnosis and the knowledge about their pathogenic properties. This study aimed to characterize clinical isolates of Candida spp. by proteomics (MALDI-TOF MS) and metabolomics (H-NMR), and to correlate their metabolic profiles with Candida species, source of infection and different virulence associated parameters. In particular, 49 Candida strains from different sources (blood, n = 15; vagina, n = 18; respiratory tract, n = 16), belonging mainly to C. albicans complex (61%), C. glabrata (20%) and C. parapsilosis (12%) species were used. Several extracellular and intracellular metabolites showed significantly different concentrations among isolates recovered from different sources of infection, as well as among different Candida species. These metabolites were mainly related to the glycolysis or gluconeogenesis, tricarboxylic acid cycle, nucleic acid synthesis and amino acid and lipid metabolism. Moreover, we found specific metabolic fingerprints associated with the ability to form biofilm, the antifungal resistance (i.e. caspofungin and fluconazole) and the production of secreted aspartyl proteinase. In conclusion, H-NMR-based metabolomics can be useful to deepen Candida spp. virulence and pathogenicity properties.
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http://dx.doi.org/10.1038/s41598-020-73889-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541501PMC
October 2020

Epidemiology of invasive pulmonary aspergillosis among COVID-19 intubated patients: a prospective study.

Clin Infect Dis 2020 Jul 28. Epub 2020 Jul 28.

Infectious Diseases Unit, Department of Medical and Surgical Sciences, Policlinico Sant'Orsola, Bologna, Italy.

Background: In this study we evaluated the incidence of invasive pulmonary aspergillosis among intubated patients with critical coronavirus disease 2019 (COVID-19) and evaluated different case definitions of invasive aspergillosis.

Methods: Prospective, multicentre study on adult patients with microbiologically confirmed COVID-19 receiving mechanical ventilation. All included participants underwent screening protocol for invasive pulmonary aspergillosis with bronchoalveolar lavage galactomannan and cultures performed on admission at 7 days and in case of clinical deterioration. Cases were classified as coronavirus associated pulmonary aspergillosis (CAPA) according to previous consensus definitions. The new definition was compared with putative invasive pulmonary aspergillosis (PIPA).

Results: A total of 108 patients were enrolled. Probable CAPA was diagnosed in 30 (27.7%) of patients after a median of 4 (2-8) days from intensive care unit (ICU) admission. Kaplan-Meier curves showed a significant higher 30-day mortality rate from ICU admission among patients with either CAPA (44% vs 19%, p= 0.002) or PIPA (74% vs 26%, p<0.001) when compared with patients not fulfilling criteria for aspergillosis. The association between CAPA [OR 3.53 (95%CI 1.29-9.67), P=0.014] or PIPA [OR 11.60 (95%CI 3.24-41.29) p<0.001] with 30-day mortality from ICU admission was confirmed even after adjustment for confounders with a logistic regression model. Among patients with CAPA receiving voriconazole treatment (13 patients, 43%) A trend toward lower mortality (46% vs 59% p=0.30) and reduction of galactomannan index in consecutive samples was observed.

Conclusion: We found a high incidence of CAPA among critically ill COVID-19 patients and that its occurrence seems to change the natural history of disease.
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http://dx.doi.org/10.1093/cid/ciaa1065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454393PMC
July 2020

Diffuse primary cutaneous infection by in a liver transplant recipient with pulmonary nocardiosis: Importance of prompt identification for clinical resolution.

Med Mycol Case Rep 2020 Jun 4;28:42-45. Epub 2020 May 4.

Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy.

Fungal infections are rare in the general population but are an emerging cause of disease in immunosuppressed patients, especially solid organ transplant recipients. Here, we report the case of a female Caucasian liver transplant patient who developed pulmonary nocardiosis two months after an episode of liver rejection. At the time of lung nocardiosis, she was being treated with tacrolimus and corticosteroids and suffered from diffuse papular skin lesions. She was initially suspected of having a cutaneous nocardial infection but culture examination revealed the presence of a dematiaceous fungus; . The prompt identification of the fungus and administration of oral Voriconazole resolved the skin infection with complete remission.
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http://dx.doi.org/10.1016/j.mmcr.2020.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218148PMC
June 2020

Occurrence of in the Blood of a Female Child With Neuroblastoma.

Front Med (Lausanne) 2020 14;7:13. Epub 2020 Feb 14.

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.

We report for the first time the occurrence of a filamentous fungus, , in the blood of a pediatric neuroblastoma patient. The genus comprises common soil-inhabiting and saprophytic fungi and has been isolated as a plant pathogen in Northern and Southern Italy. As a human pathogen, has been implicated in keratitis and can produce trichothecene toxins, which are weakly cytotoxic for mammalian cell lines. was isolated from blood during the follow-up of a previous coagulase-negative catheter-related infection. Lung nodules, compatible with fungal infection, had been observed on a CT scan 6 months earlier; they still persist. Possible routes of transmission were considered to be airborne, catheter related, or transfusion dependent, as the patient had undergone platelet and red blood cell transfusions during rescue chemotherapy. No filamentous fungi were isolated from sputum or CVCs. In conclusion, we describe an unprecedented fungemia caused by and show how an unexpected pathogen may be acquired from the environment by patients at high risk due to immunosuppression. The route of transmission remains unknown.
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http://dx.doi.org/10.3389/fmed.2020.00013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033736PMC
February 2020

HPV DNA Associates With Breast Cancer Malignancy and It Is Transferred to Breast Cancer Stromal Cells by Extracellular Vesicles.

Front Oncol 2019 16;9:860. Epub 2019 Sep 16.

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.

A causal link between Human Papillomavirus (HPV) and breast cancer (BC) remains controversial. In spite of this, the observation that HPV DNA is over-represented in the Triple Negative (TN) BC has been reported. Here we remark the high prevalence of HPV DNA (44.4%) in aggressive BC subtypes (TN and HER2+) in a population of 273 Italian women and we convey the presence of HPV DNA in the epithelial and stromal compartments by . As previously reported, we also found that serum derived-extracellular vesicles (EVs) from BC affected patients contain HPV DNA. Interestingly, in one TNBC patient, the same HPV DNA type was detected in the serum-derived EVs, cervical and BC tissue samples. Then, we report that HPV DNA can be transferred by EVs to recipient BC stromal cells that show an activated phenotype (e.g., CD44, IL6 expression) and an enhanced capability to sustain mammospheres (MS) formation. These data suggest that HPV DNA vehiculated by EVs is a potential trigger for BC niche aggressiveness.
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http://dx.doi.org/10.3389/fonc.2019.00860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756191PMC
September 2019

Saprochaete clavata infections in patients undergoing treatment for haematological malignancies: A report of a monocentric outbreak and review of the literature.

Mycoses 2019 Dec 21;62(12):1100-1107. Epub 2019 Oct 21.

Unit of Infectious Diseases, Department of Medical and Surgical Sciences, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.

Saprochaete clavata is a rare cause of fungaemia with deep organ involvement in patients with haematological malignancies with reported mortality rates of 60%-80%. We describe four cases of S clavata infection in a haematology unit over several months that were treated with voriconazole-based regimens. We also review the literature on factors that could contribute to earlier recognition and effective treatment of S clavata. We included all cases of culture-positive S clavata from sterile sites with associated signs of infection in patients undergoing treatment for a haematological malignancy. Isolates were identified by MALDI-TOF MS, and spectrum profiles were used to prepare clustering analysis of isolates. Susceptibility testing was performed using a commercial microtitre methods. Saprochaete clavata was isolated from the bloodstream in three cases and bronchial alveolar lavage (BAL) fluid in one case. Clustering analysis suggested strains of S clavata were clonal without evidence of divergence although a common source was not identified. Susceptibility testing yielded elevated MICs to fluconazole (8 mg/L) and echinocandins (>1-8 mg/L). All patients were treated with voriconazole-based regimens resulting in survival of 3/4 patients, who continued chemotherapy for their underlying malignancy without evidence of relapse. Saprochaete clavata is a rare but aggressive cause of breakthrough yeast infection in patients undergoing treatment for haematological malignancies, particularly patients with a prior history of echinocandin treatment. Timely initiation of appropriate treatment, aided by more rapid identification in microbiology laboratory, can reduce the risk of deep organ dissemination and patient death.
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http://dx.doi.org/10.1111/myc.12978DOI Listing
December 2019

Putative Role of Circulating Human Papillomavirus DNA in the Development of Primary Squamous Cell Carcinoma of the Middle Rectum: A Case Report.

Front Oncol 2019 21;9:93. Epub 2019 Feb 21.

Retired, Siena, Italy.

Here we present the case of a patient affected by rectal squamous cell carcinoma in which we demonstrated the presence of Human Papillomavirus (HPV) by a variety of techniques. Collectively, the virus was detected not only in the tumor but also in some regional lymph nodes and in non-neoplastic mucosa of the upper tract of large bowel. By contrast, it was not identifiable in its common sites of entry, namely oral and ano-genital region. We also found HPV DNA in the plasma-derived exosome. Next, by studies, we confirmed the capability of HPV DNA-positive exosomes, isolated from the supernatant of a HPV DNA positive cell line (CaSki), to transfer its DNA to human colon cancer and normal cell lines. In the stroma nearby the tumor mass we were able to demonstrate the presence of virus DNA in the stromal compartment, supporting its potential to be transferred from epithelial cells to the stromal ones. Thus, this case report favors the notion that human papillomavirus DNA can be vehiculated by exosomes in the blood of neoplastic patients and that it can be transferred, at least , to normal and neoplastic cells. Furthermore, we showed the presence of viral DNA and RNA in pluripotent stem cells of non-tumor tissue, suggesting that after viral integration (as demonstrated by p16 and RNA hybridization positivity), stem cells might have been activated into cancer stem cells inducing neoplastic transformation of normal tissue through the inactivation of p53, p21, and Rb. It is conceivable that the virus has elicited its oncogenic effect in this specific site and not elsewhere, despite its wide anatomical distribution in the patient, for a local condition of immune suppression, as demonstrated by the increase of T-regulatory (CD4/CD25/FOXP3 positive) and T-exhausted (CD8/PD-1positive) lymphocytes and the M2 polarization (high CD163/CD68 ratio) of macrophages in the neoplastic microenvironment. It is noteworthy that our findings depicted a static picture of a long-lasting dynamic process that might evolve in the development of tumors in other anatomical sites.
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http://dx.doi.org/10.3389/fonc.2019.00093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394246PMC
February 2019

Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer.

Proc Natl Acad Sci U S A 2017 10 11;114(43):E9066-E9075. Epub 2017 Oct 11.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021;

The horizontal transfer of mtDNA and its role in mediating resistance to therapy and an exit from dormancy have never been investigated. Here we identified the full mitochondrial genome in circulating extracellular vesicles (EVs) from patients with hormonal therapy-resistant (HTR) metastatic breast cancer. We generated xenograft models of HTR metastatic disease characterized by EVs in the peripheral circulation containing mtDNA. Moreover, these human HTR cells had acquired host-derived (murine) mtDNA promoting estrogen receptor-independent oxidative phosphorylation (OXPHOS). Functional studies identified cancer-associated fibroblast (CAF)-derived EVs (from patients and xenograft models) laden with whole genomic mtDNA as a mediator of this phenotype. Specifically, the treatment of hormone therapy (HT)-naive cells or HT-treated metabolically dormant populations with CAF-derived mtDNA EVs promoted an escape from metabolic quiescence and HTR disease both in vitro and in vivo. Moreover, this phenotype was associated with the acquisition of EV mtDNA, especially in cancer stem-like cells, expression of EV mtRNA, and restoration of OXPHOS. In summary, we have demonstrated that the horizontal transfer of mtDNA from EVs acts as an oncogenic signal promoting an exit from dormancy of therapy-induced cancer stem-like cells and leading to endocrine therapy resistance in OXPHOS-dependent breast cancer.
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http://dx.doi.org/10.1073/pnas.1704862114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664494PMC
October 2017

Liquid biopsy in the diagnosis of HPV DNA in breast lesions.

Future Microbiol 2018 02 4;13:187-194. Epub 2017 Oct 4.

Department of Experimental, Diagnostic & Specialty Medicine, Alma Mater Studiorum, University of Bologna, 40138, Bologna, Italy.

Aim: HPV DNA has never been investigated in nipple discharges (ND) and serum-derived extracellular vesicles, although its presence has been reported in ductal lavage fluids and blood specimens.

Materials & Methods: We analyzed 50 ND, 22 serum-derived extracellular vesicles as well as 51 pathologic breast tissues for the presence of 16 HPV DNA types.

Results: We show that the presence of HPV DNA in the ND is predictive of HPV DNA-positive breast lesions and that HPV DNA is more represented in intraductal papillomas. We also show the presence of HPV DNA in the serum-derived extracellular vesicles.

Conclusion: Our data supports the use of liquid biopsy to detect HPV DNA in breast pathology.
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http://dx.doi.org/10.2217/fmb-2017-0145DOI Listing
February 2018

Exosome-based immunomodulation during aging: A nano-perspective on inflamm-aging.

Mech Ageing Dev 2017 12 1;168:44-53. Epub 2017 Mar 1.

August Pi i Sunyer Biomedical Research Institute (IDIBAPS) and Centre of Biomedical Investigation on Diabetes and Associated Metabolic Disorders Network (CIBERDEM), 08036 Barcelona, Spain; Center of Clinical Pathology and Innovative Therapy, National Institute INRCA-IRCCS, Ancona, Italy. Electronic address:

Exosomes are nanovesicles formed by inward budding of endosomal membranes. They exert complex immunomodulatory effects on target cells, acting both as antigen-presenting vesicles and as shuttles for packets of information such as proteins, coding and non-coding RNA, and nuclear and mitochondrial DNA fragments. Albeit different, all such functions seem to be encompassed in the adaptive mechanism mediating the complex interactions of the organism with a variety of stressors, providing both for defense and for the evolution of symbiotic relationships with others organisms (gut microbiota, bacteria, and viruses). Intriguingly, the newly deciphered human virome and exosome biogenesis seem to share some physical-chemical characteristics and molecular mechanisms. Exosomes are involved in immune system recognition of self from non-self throughout life: they are therefore ideal candidate to modulate inflamm-aging, the chronic, systemic, age-related pro-inflammatory status, which influence the development/progression of the most common age-related diseases (ARDs). Not surprisingly, recent evidence has documented exosomal alteration during aging and in association with ARDs, even though data in this field are still limited. Here, we review current knowledge on exosome-based trafficking between immune cells and self/non-self cells (i.e. the virome), sketching a nano-perspective on inflamm-aging and on the mechanisms involved in health maintenance throughout life.
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http://dx.doi.org/10.1016/j.mad.2017.02.008DOI Listing
December 2017

Evolution of Cancer Stem-like Cells in Endocrine-Resistant Metastatic Breast Cancers Is Mediated by Stromal Microvesicles.

Cancer Res 2017 04 15;77(8):1927-1941. Epub 2017 Feb 15.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

The hypothesis that microvesicle-mediated miRNA transfer converts noncancer stem cells into cancer stem cells (CSC) leading to therapy resistance remains poorly investigated. Here we provide direct evidence supporting this hypothesis, by demonstrating how microvesicles derived from cancer-associated fibroblasts (CAF) transfer miR-221 to promote hormonal therapy resistance (HTR) in models of luminal breast cancer. We determined that CAF-derived microvesicles horizontally transferred miR-221 to tumor cells and, in combination with hormone therapy, activated an ER/Notch feed-forward loop responsible for the generation of CD133 CSCs. Importantly, microvesicles from patients with HTR metastatic disease expressed high levels of miR-221. We further determined that the IL6-pStat3 pathway promoted the biogenesis of onco-miR-221 CAF microvesicles and established stromal CSC niches in experimental and patient-derived breast cancer models. Coinjection of patient-derived CAFs from bone metastases led to HTR tumors, which was reversed with IL6R blockade. Finally, we generated patient-derived xenograft (PDX) models from patient-derived HTR bone metastases and analyzed tumor cells, stroma, and microvesicles. Murine and human CAFs were enriched in HTR tumors expressing high levels of CD133 cells. Depletion of murine CAFs from PDX restored sensitivity to HT, with a concurrent reduction of CD133 CSCs. Conversely, in models of CD133, HT-sensitive cancer cells, both murine and human CAFs promoted HT resistance via the generation of CD133 CSCs that expressed low levels of estrogen receptor alpha. Overall, our results illuminate how microvesicle-mediated horizontal transfer of genetic material from host stromal cells to cancer cells triggers the evolution of therapy-resistant metastases, with potentially broad implications for their control. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-2129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5392366PMC
April 2017

Self-renewal of CD133(hi) cells by IL6/Notch3 signalling regulates endocrine resistance in metastatic breast cancer.

Nat Commun 2016 Feb 9;7:10442. Epub 2016 Feb 9.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA.

The mechanisms of metastatic progression from hormonal therapy (HT) are largely unknown in luminal breast cancer. Here we demonstrate the enrichment of CD133(hi)/ER(lo) cancer cells in clinical specimens following neoadjuvant endocrine therapy and in HT refractory metastatic disease. We develop experimental models of metastatic luminal breast cancer and demonstrate that HT can promote the generation of HT-resistant, self-renewing CD133(hi)/ER(lo)/IL6(hi) cancer stem cells (CSCs). HT initially abrogates oxidative phosphorylation (OXPHOS) generating self-renewal-deficient cancer cells, CD133(hi)/ER(lo)/OXPHOS(lo). These cells exit metabolic dormancy via an IL6-driven feed-forward ER(lo)-IL6(hi)-Notch(hi) loop, activating OXPHOS, in the absence of ER activity. The inhibition of IL6R/IL6-Notch pathways switches the self-renewal of CD133(hi) CSCs, from an IL6/Notch-dependent one to an ER-dependent one, through the re-expression of ER. Thus, HT induces an OXPHOS metabolic editing of luminal breast cancers, paradoxically establishing HT-driven self-renewal of dormant CD133(hi)/ER(lo) cells mediating metastatic progression, which is sensitive to dual targeted therapy.
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http://dx.doi.org/10.1038/ncomms10442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4748123PMC
February 2016

Carbonic Anhydrase 9 mRNA/microRNA34a Interplay in Hypoxic Human Mammospheres.

J Cell Physiol 2016 Jul 30;231(7):1534-41. Epub 2015 Nov 30.

Center for Applied Biomedical Research (CRBA), St. Orsola-Malpighi University Hospital, Bologna, Italy.

The hypoxic environment is a crucial component of the cancer stem cell niche and it is capable of eliciting stem cell features in cancer cells. We previously reported that SNAI2 up-regulates the expression of Carbonic Anhydrase iso-enzyme 9 (CA9) in hypoxic MCF7 cells. Here we show that SNAI2 down-regulates miR34a expression in hypoxic MCF7 cell-derived mammospheres. Next, we report on the capability of miR34a to decrease CA9 mRNA stability and CA9 protein expression. We also convey that the over-expression of cloned CA9-mRNA-3'UTR increases the mRNA half-life and protein levels of two miR34a targets JAGGED1 and NOTCH3. The data here reported shows that the SNAI2-dependent down-regulation of miR34a substantially contributes to the post-transcriptional up-regulation of CA9, and that CA9-mRNA-3'UTR acts as an endogenous microRNA sponge. We conclude that CA9/miR34 interplay shares in the hypoxic regulation of mammospheres and therefore, may play a relevant role in the hypoxic breast cancer stem cell niche.
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http://dx.doi.org/10.1002/jcp.25245DOI Listing
July 2016

DNA damage response (DDR) and senescence: shuttled inflamma-miRNAs on the stage of inflamm-aging.

Oncotarget 2015 Nov;6(34):35509-21

Department of Experimental, Diagnostic and Specialty Medicine, DIMES, University of Bologna, Bologna, Italy.

A major issue in aging research is how cellular phenomena affect aging at the systemic level. Emerging evidence suggests that DNA damage response (DDR) signaling is a key mechanism linking DNA damage accumulation, cell senescence, and organism aging. DDR activation in senescent cells promotes acquisition of a proinflammatory secretory phenotype (SASP), which in turn elicits DDR and SASP activation in neighboring cells, thereby creating a proinflammatory environment extending at the local and eventually the systemic level. DDR activation is triggered by genomic lesions as well as emerging bacterial and viral metagenomes. Therefore, the buildup of cells with an activated DDR probably fuels inflamm-aging and predisposes to the development of the major age-related diseases (ARDs). Micro (mi)-RNAs - non-coding RNAs involved in gene expression modulation - are released locally and systemically by a variety of shuttles (exosomes, lipoproteins, proteins) that likely affect the efficiency of their biological effects. Here we suggest that some miRNAs, previously found to be associated with inflammation and senescence - miR-146, miR-155, and miR-21 - play a central role in the interplay among DDR, cell senescence and inflamm-aging. The identification of the functions of shuttled senescence-associated miRNAs is expected to shed light on the aging process and on how to delay ARD development.
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http://dx.doi.org/10.18632/oncotarget.5899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742121PMC
November 2015

High-throughput genotyping of high-risk Human Papillomavirus by MALDI-TOF Mass Spectrometry-based method.

New Microbiol 2015 Apr 29;38(2):211-23. Epub 2015 Apr 29.

Center for Applied Biomedical Research - CRBA, University Hospital S.Orsola-Malpighi, Via Massarenti 9, 40138, Bologna, Italy.

A high-throughput matrix-assisted laser desorption ionisation-time of flight (MALDI-TOF) mass spectrometry (MS)-based method was here developed to genotype 16 high-risk human papillomavirus (HPV) types in cervical cytology specimens. This method was compared to a commercial kit, the Inno-LiPA HPV genotyping assay, which detects a broad spectrum of HPV types. HPV DNA was assessed by the two methods in a total of 325 cervical cytology specimens collected in PreservCyt® solution. The overall agreement was almost perfect (Cohen's k=0.86) in term of positive and negative cases. Indeed, HPV types 16, 35, 56 and 66 showed the highest agreement values (>0.80). The highest agreement values (K >0.80) were found for all 16 HPV types in single infections, but only for HPV 16, 35, 45 and 56 in multiple infections. In conclusion, the high-throughput MS-based method developed here is well-suited for broad spectrum HPV genotyping in large-scale epidemiological studies.
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April 2015

Human papillomavirus infection and pathogenic mitochondrial DNA mutation in bilateral multinodular oncocytic hyperplasia of the parotid.

Pathology 2014 Apr;46(3):250-3

1U. O. Genetica Medica, Dip. di Scienze Mediche e Chirurgiche 2U. O. Anatomia e Istologia Patologica 3Dipartimento di Medicina Clinica Diagnostica e Sperimentale 4U. O. Otorinolaringoiatria, Policlinico Universitario S. Orsola-Malpighi, Università di Bologna, Bologna, Italy.

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http://dx.doi.org/10.1097/PAT.0000000000000079DOI Listing
April 2014

Evidence of association of human papillomavirus with prognosis worsening in glioblastoma multiforme.

Neuro Oncol 2014 Jan 26;16(2):298-302. Epub 2013 Nov 26.

Corresponding author: Giuseppe Gasparre, PhD, Dipartimento di Scienze Mediche e Chirurgiche, UO Genetica Medica, Pad.11, Policlinico S.Orsola-Malpighi, via Massarenti 9, 40138, Bologna, Italy.

Background: Glioblastoma multiforme (GBM) is the most malignant brain tumor in adults, but its etiology still remains unknown. Recently, a role of viruses such as cytomegalovirus and JC virus in gliomagenesis has been suggested. Since human papillomavirus (HPV) is considered the most common oncogenic virus in humans, we evaluated its occurrence in GBM samples.

Material And Methods: Fifty-two formalin-fixed paraffin-embedded primary glioblastoma specimens were retrospectively analyzed. The presence of HPV genome on tumor DNA was assessed by MY/GP nested PCR. Confirmation of HPV detection was obtained by chromogenic in situ hybridization (CISH) and immunohistochemistry (IHC) with an antibody directed against the L1 capsidic protein. Finally, univariate and multivariate proportional-hazards models were used to compare the risk of death among HPV-positive and HPV-negative patients.

Results: Strikingly, viral DNA was detected after PCR in 12 cases (23%). HPV16 genome was present in 25% infected samples, whereas the remaining samples tested positive for HPV6. CISH confirmed positivity in all infected samples for which enough material was available. Moreover, IHC positivity suggested that production of viral proteins from HPV genome is an ongoing process in GBM cancer cells. Finally an association between HPV infection and a worse prognosis was found in patients upon age stratification with a univariate analysis (HR, 2.10; 95% CI, 1.00-4.44; log-rank P = .045).

Conclusions: HPV infection status may be considered an independent prognostic factor in GBM patients and suggests that prevention may be considered, should HPV be recognized as a causative agent in gliomagenesis.
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http://dx.doi.org/10.1093/neuonc/not140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895373PMC
January 2014

Comparison of the antibacterial activity of an ozonated oil with chlorhexidine digluconate and povidone-iodine. A disk diffusion test.

New Microbiol 2013 Jul 30;36(3):289-302. Epub 2013 Jun 30.

Department of Periodontology and Implantology, School of Dentistry, Alma Mater Studiorum.

Ozonated oils are antiseptics obtained from the chemical reaction between ozone and unsaturated fatty acids of vegetable oils. The aim of this study was to investigate the antimicrobial effectiveness of a commercially available ozonated oil (O3-Oil), in comparison with 0.2% chlorhexidine digluconate (CHX) and 10% povidone-iodine (PVP-I) through a disk diffusion test. For each antiseptic a series of two-fold dilutions was made, obtaining seven dilutions: 1:2, 1:4, 1:8, 1:16, 1:32, 1:64 and 1:128. The undiluted antiseptics and the seven dilutions were tested against two freeze-dried bacterial strains: Staphylococcus aureus (Sa) and Porphyromonas gingivalis (Pg). O3-Oil showed significantly greater diameters of growth inhibition (p<0.01) than CHX and PVP-I in all dilutions for both tested strains. CHX lost any antibacterial efficacy when diluted more than 1:32. At the highest dilution, the diameters of growth inhibition against Sa were 20.67±0.58 mm and 15.33±0.58 mm, for O3-Oil and PVP-I, respectively. At the same dilution, the diameters of growth inhibition against Pg were: 19.00 mm for O3-Oil and 13.67±0.58 mm for PVP-I. The promising results obtained for the O3-Oil, against the opportunistic Sa, and Pg, one of the main periodontal pathogens, suggest its potential applicability for periodontal treatment. Further preclinical and clinical investigations are warranted.
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July 2013

Prevalence of R5 strains in multi-treated HIV subjects and impact of new regimens including maraviroc in a selected group of patients with CCR5-tropic HIV-1 infection.

Int J Infect Dis 2013 Oct 15;17(10):e875-82. Epub 2013 Apr 15.

Department of Experimental, Diagnostic and Specialty Medicine, School of Medicine, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy.

Objectives: Maraviroc currently represents an important antiretroviral drug for multi-experienced and viremic HIV patients. This study focused on two main points: (1) determining the prevalence of R5 and X4 HIV strains in antiretroviral-experienced patients using two main tests currently in use to determine viral tropism, and (2) the follow-up to 3 years of a limited number of patients who started a new antiretroviral protocol including maraviroc.

Methods: A group of 56 HIV patients, previously multi-treated, were first analyzed by genotyping assay and Trofile™ to establish their eligibility for maraviroc treatment. In addition, 25 subjects selected to follow a new therapeutic protocol including a CCR5 antagonist were monitored by HIV RNA viral load and CD4+ cell count.

Results: The determination of viral tropism showed a large percentage of patients with an R5 profile (72% by genotyping assay and 74% by Trofile). The follow-up of most (21 out 25) patients who started the new antiretroviral protocol showed an undetectable viral load throughout the observation period, accompanied by a major improvement in CD4 cell count (cells/mm(3)) (baseline: median CD4 cell count 365, interquartile range (IQR) 204-511; 12 months: median value 501, IQR 349-677, p=0.042; 24 months: median value 503, IQR 386-678, p=0.026; 36 months: median value 601, IQR 517-717, p=0.001). Among the four non-responder subjects, two showed a lack of drug compliance and two switched from R5 to X4.

Conclusion: Although our patient cohort was small, the results showed a high prevalence of R5 viral strains in multi-experienced patients. As well as showing the advantages of genotyping, which can be performed in plasma samples with low viral load replication, the follow-up of HIV patients selected for an alternative drug protocol, including a CCR5 antagonist, showed a persistent undetectable viral replication and a good recovery of CD4 cell count in most treated HIV patients.
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http://dx.doi.org/10.1016/j.ijid.2013.02.020DOI Listing
October 2013

Comparison of Abbott RealTime High Risk HPV and Hybrid Capture 2 for the detection of high-risk HPV DNA in a referral population setting.

J Clin Virol 2012 Feb 23;53(2):121-4. Epub 2011 Nov 23.

Department of Haematology, Oncology an Laboratory Medicine, Section of Microbiology, S. Orsola-Malpighi Hospital, University of Bologna, via Massarenti 9, 40138 Bologna, Italy.

Background: The Abbott RealTime High Risk HPV assay (ART) is an automated multiplex real-time PCR test for detection of DNA from 14 high risk (HR) HPV types in cervical specimens and simultaneous distinction of HPV16 and HPV18 from other HR-HPV.

Objectives: To evaluate the performance of the ART assay in specimens referred for HPV testing to our laboratory (referral population) by comparison with historical data from HC2 and INNO-LiPA as well as histological status, if available.

Study Design: 412 cervical specimens were collected from women between 18 and 70 years of age: 301 previously tested by HC2 without clinical data and 111 previously tested by HC2 and INNO-LiPA with histological diagnosis of CIN3+.

Results: Our study demonstrated good overall agreement between ART, HC2 and INNO-LiPA. In the group of the CIN3+ specimens HR-HPV was detected by ART in 93.07% (95% CI: 88.12-98.02), while HR-HPV detection rates with HC2 and INNO-LiPA were 91.09% (95% CI: 85.53-96.65) and 95.05% (95% CI: 90.82-99.28), respectively. The typing capability of ART for HPV16, HPV18 and a pool of twelve other HR-HPV types was investigated by comparison with INNO-LiPA demonstrating high overall assay concordance (89.81%; k 0.87).

Conclusions: The Abbott RealTime assay showed similar clinical performance for detection of CIN3+ compared with HC2. The high level of automation and ability to identify HPV16, HPV18 and other HR-HPV make this assay a very attractive option for HR-HPV testing, potentially improving patient management by risk stratification of cytological abnormal populations.
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http://dx.doi.org/10.1016/j.jcv.2011.10.016DOI Listing
February 2012

Molecular analysis of HPV 16 E6I/E6II spliced mRNAs and correlation with the viral physical state and the grade of the cervical lesion.

J Med Virol 2009 Jul;81(7):1276-82

Department of Haematology and Oncological Sciences L. e A. Seragnoli, Microbiology Section, University of Bologna, Bologna, Italy.

The presence of HPV 16 E6*I/E6*II spliced transcripts, in cervical lesions of different grade, was analyzed to characterize the transcription pattern. The presence and amount of spliced transcripts were correlated with DNA viral markers such as E2/E6 ratio and physical state. The detection of HPV 16 E6*I/E6*II mRNAs was set up by an SYBR Green real-time reverse transcriptase PCR assay with an optimal dynamic range and sensitivity. The assay was applied to the analysis of 71 specimens, positive to HPV 16 as a sole infection, from women with abnormal cervical smears, precisely 31 low-grade squamous intraepithelial lesions and 40 high-grade lesions. Samples negative to both transcripts were found only in low-grade cervical lesions. Three different transcription profiles were found in the low- and high-grade lesions analyzed: in low-grade lesions samples positive only to E6*II and in high-grade lesions samples positive only to E6*I were detected. In low- and high-grade lesions, samples positive to both E6*I and E6*II were found. In the samples positive for both transcripts, the E6*I/E6*II ratio was higher than that in the majority of high-grade lesions and lower than that in all the low-grade lesions. Analyzing the transcription pattern in relation to E2/E6 ratio and to the DNA physical state, the presence of high values of E6*I was associated mainly with low values of E2/E6 ratio and of mixed DNA forms. The detection of HPV 16 E6*I/E6*II mRNAs may serve to identify transcription patterns indicative of cervical disease progression and help physicians to decide clinical management.
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http://dx.doi.org/10.1002/jmv.21496DOI Listing
July 2009

High-throughput two-step LNA real time PCR assay for the quantitative detection and genotyping of HPV prognostic-risk groups.

J Clin Virol 2009 Aug 26;45(4):304-10. Epub 2009 May 26.

Division of Microbiology, University of Bologna, Policlinico S. Orsola-Malpighi, via Massarenti 9, 40138 Bologna, Italy.

Background: Human papillomavirus (HPV) infection is a necessary event in the development of cervical carcinoma. High risk (HR) HPV genotypes, however, may progress differentially from low grade lesions to malignancy.

Objectives: The necessity to genotype and quantify HPV-DNA in cervical screening programs, in the follow up post-surgical treatments and in monitoring the effectiveness of HPV vaccination programs, requires access to economical, high-throughput and flexible molecular technologies.

Study Design: A high-throughput two-step LNA real time PCR assay was developed consisting of real time PCR reactions with fluorescent Locked Nucleic Acid (LNA) probes. The first step permits classification into three prognostic-risk groups of nine HR HPV genotypes (16, 18, 31, 33, 35, 45, 52, 56 and 58) most frequently found associated with cervical lesions in Europe. The second step allows us to genotype/quantify the HPV-DNA only when clinical, epidemiological or prophylactic aims exist.

Results: The specificity, repeatability, detection and quantitation limit, and linearity of the assay were evaluated and appear to be in agreement with guidelines for the validation of analytical procedures. The overall genotype concordance on cervical samples between our assay and INNOLiPA test was 94% (k 0.83) indicating good agreement.

Conclusions: The two-step PCR assay can give much information relative to the predictive value of different HR HPV types and can quantify the genotype-specific viral load. In particular, its ability to detect and quantify nine HR HPV genotypes can help provide more efficient and successful patient care and may be useful for the monitoring of the efficacy of HPV vaccines.
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http://dx.doi.org/10.1016/j.jcv.2009.04.021DOI Listing
August 2009

Disruption of HPV 16 E1 and E2 genes in precancerous cervical lesions.

J Virol Methods 2009 Jun 31;158(1-2):180-3. Epub 2009 Jan 31.

Department of Haematology and Oncological Sciences L e A Seragnoli, Microbiology Section, University of Bologna, Italy.

The presence of HPV 16 E1 and E2 genes was detected in cervical cytological samples using polymerase chain reaction assays. A total of 48 samples were analyzed from patients with HPV 16 infections associated with 13 low-grade cervical intraepithelial neoplasia and 35 high-grade cervical intraepithelial neoplasia. Disruption/deletion sites, within E1 and E2 genes, were detected using 6 primer pairs spanning the entire gene sequences. This technique is not able to recognize mixed DNA forms (integrated plus episomal DNA); therefore, it detects only the presence of pure integrated DNA. Both E1 and E2 genes were detected in 84.6% and in 62.9% of low and high-grade lesions, respectively. The rate of samples with disrupted/deleted genes was significantly higher in high-grade cervical intraepithelial neoplasia than in low-grade cervical intraepithelial neoplasia (P<0.05). In high-grade cervical intraepithelial neoplasia the disruption/deletion pattern involved both E1 and E2 genes and E2 gene was always involved, while in the low grade cervical intraepithelial neoplasia only E1 gene was involved. In conclusion, in high-grade cervical lesions E2 gene seems a suitable target to identify HPV 16 DNA integration into cellular genome.
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http://dx.doi.org/10.1016/j.jviromet.2009.01.005DOI Listing
June 2009

Rapid and sensitive detection of MS2 coliphages in wastewater samples by quantitative reverse transcriptase PCR.

New Microbiol 2008 Apr;31(2):273-80

Department of Clinical and Experimental Medicine, Division of Microbiology, University of Bologna, Ozzano Emilia, Italy.

Coliphage MS2 is used in place of pathogens in many studies and is considered one of the indicators of pathogenetic viruses in wastewater. We developed a quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) assay to quantify MS2 coliphages in treated wastewater samples. The format used was SYBR Green. The assay included an internal control to disclose the presence of PCR-product inhibitors. The method had a wide dynamic range (8 logs) with a correlation coefficient of 0.999 and is capable of detecting as few as 4x10(2) genome equivalents/100 ml of wastewater sample. The method was validated by using artificially contaminated water samples. The validated method was then applied to naturally contaminated samples collected in a wastewater treatment plant and the results were compared with those obtained by a plaque assay. In comparison with the plaque assay the PCR-method yielded viral counts about 1.5 orders of magnitude higher. The entire detection method, including sample processing and real-time PCR amplification, was completed within 4 hours, making it a rapid single-day method.
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April 2008

Correlation of high-risk human papillomavirus genotypes persistence and risk of residual or recurrent cervical disease after surgical treatment.

J Med Virol 2008 Aug;80(8):1434-40

Division of Microbiology, University of Bologna, Bologna, Italy.

The evidence on genotype-specific risk in women infected with human papillomavirus (HPV) with normal cytology and the importance of the distinction of high-risk (HR)-HPV genotypes in the management of low-grade lesions suggest that the distinction of HR-HPV genotypes has the potential to improve the follow-up of patients treated for high-grade cervical lesions. The aims of this study were to define the persistence of the different HR-HPV in the follow-up of surgical treated women, to detect the changes of genotypes from the pre- to the post-operative status, and to evaluate whether genotype-specific persistence can predict the development of residual or recurrent disease during the follow-up. HR-HPV detection and genotyping was carried out by the Linear Array HPV Genotyping Test on cervical cytological samples from 72 women treated by surgery. The 6-month post-operative HPV status was correlated with the pre-operative HPV genotype and with the residual or recurrent disease within 24 months. It was observed that the residual or recurrent disease in women with persistence of HPV 16 and/or HPV 18 was higher (82.4%) than in women with persistence of at least one HR-HPV type of group 2 (HPV 31, 33, 35, 45, 52, and 58) (66.7%) and at least one type of group 3 (HPV 39, 51, 56, 59, 68, 26, 53, 66, 73, and 82) (14.3%). These data defined HR-HPV groups for the risk of progression of disease and suggested that the identification of persistent infection with different HR-HPV genotypes has the potential to improve the management of these patients.
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http://dx.doi.org/10.1002/jmv.21198DOI Listing
August 2008

Viral DNA load, physical status and E2/E6 ratio as markers to grade HPV16 positive women for high-grade cervical lesions.

Gynecol Oncol 2007 Sep 13;106(3):549-57. Epub 2007 Jun 13.

Department of Clinical and Experimental Medicine, Microbiology Section, University of Bologna, and Department of Obstetrics and Gynecology, S. Orsola-Malpighi Hospital, Italy.

Objectives: Cervical intraepithelial neoplasias (CIN) associated with high-risk (HR) human papillomavirus infection, in addition to HR-HPV typing need other viral marker testing to distinguish a subset of lesions with clinical relevant infections. This study has evaluated the significance of viral markers, such as viral load, physical status and E2/E6 ratio, to stratify HPV16 infected women at a single point in time for grade of cervical lesions.

Methods: One hundred sixty-six cytological specimens were selected from women with low (n=72) and high (n=94) grade squamous intraepithelial lesions (SIL), and positive to HPV16. All the 72 LSIL were CINI, 83 of the 94 HSIL were CINII/III and 11 SCC (Squamous Cervical Carcinoma). Cytological specimens were analysed by two different SYBR Green Real-time PCR assays (RT-PCR). Specific primers for both E2 and E6 viral genes and GAPDH cellular gene were designed to determine viral load, physical status and E2/E6 ratio.

Results: The viral load was significantly higher in HSIL than in LSIL. In CINI episomal DNA was prevalent (72.2%), mixed forms (episomal and integrated) were 27.8%, suggestive of an early integration of viral DNA into cellular genome, no pure integrated forms were detected. However in CINII/III mixed DNA forms were prevalent (73.5%). In SCC pure integrated DNA was prevalent (81.8%) in absence of episomal forms. E2/E6 ratio decreased significantly from CINI to CINII/III and SCC with a linear trend. The logistic regression analysis showed that viral load higher than 1.38x10(6) genome copies per 300 ng of total DNA associated with E2/E6 ratio lower than 0.90 was highly significant in differentiating CINII/III versus CINI, while the only E2/E6 value lower than 0.17 was significant in differentiating SCC from CINI.

Conclusions: Viral load higher than 1.38x10(6) genome copies per 300 ng of total DNA and E2/E6 ratio values allow HPV16 infected women with high grade cervical intraepithelial lesions to be recognized.
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http://dx.doi.org/10.1016/j.ygyno.2007.05.004DOI Listing
September 2007

HPV DNA patterns and disease implications in the follow-up of patients treated for HPV16 high-grade carcinoma in situ.

J Med Virol 2006 Apr;78(4):494-500

Department of Clinical and Experimental Medicine, Microbiology Section, University of Bologna, Bologna, Italy.

Twenty-five patients with high-grade cervical lesions associated with HPV16 infection were studied at the time of surgical treatment and followed up after conization. Before surgical treatment, the following parameters were analyzed: (1) physical status of HPV16 DNA, (2) viral load, (3) cytological presentation confirmed by histological diagnosis, and (4) colposcopy. At the time of conization, (5) margin presentation, and (6) cone biopsy were evaluated. At each stage of the follow-up (7) physical status of HPV16 DNA, (8) viral load, (9) cytological test, and (10) colposcopy were repeated. The correlation between the different parameters was examined. Significant differences in the viral loads were observed between integrated and episomal forms and between the coexisting integrated/episomal forms and the only episomal form, while no statistically significant differences were observed between integrated and coexisting forms. At the first stage of follow-up, 11 of 25 patients analyzed (44%) were negative to HPV DNA cytology and colposcopy tests, 13 of the 25 (52%) were HPV16 DNA negative, 17 (68%) cytology negative, and 20 (80%) colposcopy negative. At the closing stage, 15 of 25 subjects (60%) were negative to all three tests, 16 of the 25 (64%) were HPV16 DNA negative, 19 (76%) cytology negative, and 20 colposcopy negative (80%). These observations suggest that in surgery treated patients the viral clearance at the closing stage of follow-up was unrelated to the HPV DNA physical status and to the viral load before treatment, but was associated significantly with the effectiveness of surgery treatment, in particular with margin cone presentation.
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http://dx.doi.org/10.1002/jmv.20567DOI Listing
April 2006