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Background: Works of art may serve as a source of evidence of diseases and help to better understand their natural history. Summary: Bernardino da Fossa was a 15th-century Italian Franciscan friar who wrote sermons and historical works. He described the events of the Observance Reformation movement since its dawn, but the last chapter is unexplainably interrupted. This has been considered suggestive for an acute and disabling illness. A painting dating back 12 years after his death depicts Bernardino holding a crutch with his left arm. This may represent an important clue to establish a gait disturbance, whereas the permanent interruption in drafting his writing may be ascribed to a serious writing impairment. Key Messages: The historical detail of the writing suspension and the crutch in this painting represent important hints of the stroke suffered by Bernardino da Fossa.

To investigate variation in ancient DNA recovery of Brucella melitensis, the causative agent of brucellosis, from multiple tissues belonging to one individual MATERIALS: 14 samples were analyzed from the mummified remains of the Blessed Sante, a 14Shotgun sequencing data from was examined to determine the presence of Brucella DNA.Three of the 14 samples contained authentic ancient DNA, identified as belonging to B. melitensis. A genome (23.81X depth coverage, 0.98 breadth coverage) was recovered from a kidney stone. Nine of the samples contained reads classified as B. melitensis (7-169), but for many the data quality was insufficient to withstand our identification and authentication criteria.We identified significant variation in the preservation and abundance of B. melitensis DNA present across multiple tissues, with calcified nodules yielding the highest number of authenticated reads. This shows how greatly sample selection can impact pathogen identification.Our results demonstrate variation in the preservation and recovery of pathogen DNA across tissues. This study highlights the importance of sample selection in the reconstruction of infectious disease burden and highlights the importance of a holistic approach to identifying disease.Study focuses on pathogen recovery in a single individual.Further analysis of how sampling impacts aDNA recovery will improve pathogen aDNA recovery and advance our understanding of disease in past peoples.

The inner Abruzzo region, corresponding to the province of L’Aquila, is a land of mountains and highlands in central Italy. Its environmental conditions greatly foster spontaneous mummification, and the area is well known for the human mummies found in the last decades. We present a newly discovered collection of mummified remains in the village of Calascio, located 1,210 meters above sea level, near Gran Sasso Mountain. Here, the Franciscan convent of Santa Maria delle Grazie was built in 1594. The preliminary survey of a crypt in the conventual church allowed us to observe wooden coffins with at least seven mummified bodies still in their clothes, and several bony remains. Most likely, the mummies date back to the second half of the 19th century, and belonged to laypersons. Preservation was certainly due to the cold dry environment of the crypt. The recovery of the entire series will take place through speleological techniques according to stratigraphic relationships, in order to trace a bioanthropological profile of this small community members.

The renal stone found in the natural mummy of an anonymous nobleman dating to 19

Giant cell tumor (GCT) of the bone is a locally aggressive and rarely metastasizing neoplasm. It is composed of neoplastic mononuclear stromal cells with a monotonous appearance admixed with macrophages and osteoclast-like giant cells. In a small subset of cases, GCT is malignant. Terminology previously related to this entity, and which is no longer supported by the World Health Organization, includes osteoclastoma and benign fibrous histiocytoma (BFH). Giant cells occur in numerous other pathologic conditions of the bone, which accounts for the misrepresentation of these non-GCT tumors in the early literature. Non-ossifying fibroma (NOF), aneurysmal bone cyst, and chondroblastoma have been erroneously labeled GCT for this reason. A single description of an ancient GCT was reported by Brothwell and Sandison and subsequently mentioned by Aufderheide and Rodrìguez-Martìn who were astonished that more of these tumors had not been identified in archaeological cases. To the best of our knowledge, no other cases of ancient GCT have been cited in the paleopathology literature. The study of this type of neoplasm in antiquity can be used as a means to better understand its characteristics and behavior and to expand the depth of time of the etiology of these lesions. We report a case of GCT of the left femur observed following the total body CT imaging of a partially mummified adult female, dating to eighteenth century.

Celestine V is considered one of the most enigmatic Popes. He has been the subject of much speculation, with legends claiming he was murdered by order of his successor Boniface VIII. Assassination rumors first started in medieval times, but they were renewed in 1630 by the discovery of a nail that fitted perfectly into a square opening in his skull. During the latest Canonical Recognition, the morphology of the lesion was examined by visual inspection, showing it could not have been produced during life. The legend that the nail was driven through the Pope’s head may finally be discredited.

The diagnosis of acute toxoplasmic lymphadenitis is traditionally based on the combination of lymph node excisional biopsy with specific tests. The classic triad (marked follicular hyperplasia, small irregular clusters of epithelioid histiocytes in germinal centers, and sinusoidal distension by monocytoid B lymphocytes) is considered diagnostic of the so-called Piringer-Kuchinka lymphadenitis. Toxoplasma gondii organisms have been exceptionally disclosed in such histopathological setting, establishing the diagnosis of toxoplasmic lymphadenitis. Two cases of Piringer-Kuchinka lymphadenitis with toxoplasma cyst demonstration are reported, along with a complete review of the literature.

Simple Summary PCNA is an interesting target for cancertreatment due to its essential activities in DNA replication and repair and its recently discovered regulatory roles in cellular signaling. Here, we demonstrate that ATX-101, a peptide targeting PCNA, has antitumor effects as a single agent and radiosensitizing properties in glioblastoma multiforme models. Abstract Cell proliferation requires the orchestrated actions of a myriad of proteins regulating DNA replication, DNA repair and damage tolerance, and cell cycle. Proliferating cell nuclear antigen (PCNA) is a master regulator which interacts with multiple proteins functioning in these processes, and this makes PCNA an attractive target in anticancer therapies. Here, we show that a cell-penetrating peptide containing the AlkB homolog 2 PCNA-interacting motif (APIM), ATX-101, has antitumor activity in a panel of human glioblastoma multiforme (GBM) cell lines and patient-derived glioma-initiating cells (GICs). Their sensitivity to ATX-101 was not related to cellular levels of PCNA, or p53, PTEN, or MGMT status. However, ATX-101 reduced Akt/mTOR and DNA-PKcs signaling, and a correlation between high Akt activation and sensitivity for ATX-101 was found. ATX-101 increased the levels of γH2AX, DNA fragmentation, and apoptosis when combined with radiotherapy (RT). In line with the in vitro results, ATX-101 strongly reduced tumor growth in two subcutaneous xenografts and two orthotopic GBM models, both as a single agent and in combination with RT. The ability of ATX-101 to sensitize cells to RT is promising for further development of this compound for use in GBM.

Summary The diagnosis of acute toxoplasmic lymphadenitis is traditionally based on the combination of lymph node excisional biopsy with specific tests. The classic triad (marked follicular hyperplasia, small irregular clusters of epithelioid histiocytes in germinal centers, and sinusoidal distension by monocytoid B lymphocytes) is considered diagnostic of the so-called Piringer-Kuchinka lymphadenitis. Toxoplasma gondii organisms have been exceptionally disclosed in such histopathological setting, establishing the diagnosis of toxoplasmic lymphadenitis. Two cases of Piringer-Kuchinka lymphadenitis with toxoplasma cyst demonstration are reported, along with a complete review of the literature.

NFκB is implicated in breast cancer bone metastasis and skeletal remodelling. However, the role of IKKβ, a key component of the canonical NFκB pathway, in the regulation of breast cancer osteolytic metastasis has not been investigated. Here, we describe the cancer-specific contribution of IKKβ to bone metastasis, skeletal tumour growth and osteolysis associated with breast cancer. IKKβ is highly expressed in invasive breast tumours and its level of expression was higher in patients with bone metastasis. IKKβ overexpression in parental MDA-MD-231 breast cancer cells, promoted mammary tumour growth but failed to convey osteolytic potential to these cells in mice. In contrast, IKKβ overexpression in osteotropic sub-clones of MDA-MB-231 cells with differing osteolytic phenotypes increased incidence of bone metastasis, exacerbated osteolysis and enhanced skeletal tumour growth, whereas its knockdown was inhibitory. Functional and mechanistic studies revealed that IKKβ enhanced the ability of osteotropic MDA-MB-231 cells to migrate, increase osteoclastogenesis, and to inhibit osteoblast differentiation via a mechanism mediated, at least in part, by cytoplasmic sequestering of FoxO3a and VEGFA production. Thus, tumour-selective manipulation of IKKβ and its interaction with FoxO3a may represent a novel strategy to reduce the development of secondary breast cancer in the skeleton.

Peroxisome proliferator-activated receptor alpha (PPARα) has been involved in the regulation of somatotroph tumour cells and may be targeted by different drugs, some of them are in current clinical use. The aim of this study was to investigate the expression of PPARα in additional phenotypes of pituitary adenomas (PA), the relationship between PPARα and its potential molecular partner aryl hydrocarbon receptor interacting protein (AIP) in these tumours, and the effects of PPARα agonists on lactotroph cells. Seventy-five human PA – 57 non-functioning (NFPA) and 18 prolactinomas (PRL-PA) – were characterised for PPARα and AIP expression by real time RT-PCR and/or immunohistochemistry (IHC), and the effects of fenofibrate and WY 14 643 on MMQ cells were studied in vitro. PPARα was expressed in a majority of PA. PPARα immunostaining was observed in 93.7% PRL-PA vs. 60.6% NFPA (p=0.016), the opposite being found for AIP (83.3% in NFPA vs. 43.7% in PRL-PA, p=0.003). PPARα expression was unrelated to gonadotroph differentiation in NFPA, but positively correlated with tumour volume in PRL-PA. Both drugs significantly reduced MMQ cell growth at high concentrations (100–200 μM). At the same time, despite modest stimulating effects on PRL secretion were observed, these were overcome by the reduction in cell number. In conclusion, PPARα is commonly expressed by PRL-PA and NFPA, regardless of AIP, and may represent a new target of PPARα agonists.

The role of histone deacetylase (HDAC) 4 and 6 in glioblastoma (GBM) radioresistance was investigated. We found that tumor samples from 31 GBM patients, who underwent temozolomide and radiotherapy combined treatment, showed HDAC4 and HDAC6 expression in 93.5% and 96.7% of cases, respectively. Retrospective clinical data analysis demonstrated that high-intensity HDAC4 and/or HDAC6 immunostaining was predictive of poor clinical outcome. In vitro experiments revealed that short hairpin RNA-mediated silencing of HDAC4 or HDAC6 radiosensitized U87MG and U251MG GBM cell lines by promoting DNA double-strand break (DSBs) accumulation and by affecting DSBs repair molecular machinery. We found that HDAC6 knock-down predisposes to radiation therapy-induced U251MG apoptosis- and U87MG autophagy-mediated cell death. HDAC4 silencing promoted radiation therapy-induced senescence, independently by the cellular context. Finally, we showed that p53WT expression contributed to the radiotherapy lethal effects and that HDAC4 or HDAC6 sustained GBM stem-like radioresistant phenotype. Altogether, these observations suggest that HDAC4 and HDAC6 are guardians of irradiation-induced DNA damages and stemness, thus promoting radioresistance, and may represent potential prognostic markers and therapeutic targets in GBM.

Besides its role as oxygen transporter, recent findings suggest that haemoglobin beta (HBB) may have roles in other contexts. We evaluated the impact of HBB expression in primary human breast cancers, and in breast cancer cell lines overexpressing HBB by in vitro and in vivo studies. Publicly available microarray databases were used to perform multivariate survival analyses. A significantly higher expression of HBB was observed in invasive carcinoma histotypes vs in situ counterparts, along with a positive correlation between HBB and the Ki67 proliferation marker. HBB-overexpressing breast cancer cells migrate and invade more, show HIF-1α upregulation and their conditioned media enhances angiogenesis. Blocking the oxygen-binding site of HBB reverts the increase of migration and HIF-1α upregulation observed in HBB-overexpressing breast cancer cells. Orthotopically implanted MDA-MB-231 overexpressing HBB (MDA-HBB) generated tumours with faster growth rate and increased neoangiogenesis. Moreover, local recurrence and visceral metastases were observed only in MDA-HBB-implanted mice. Similar results were observed with 4T1 mouse breast cancer cells. Finally, bioinformatics analyses of public data sets correlated high HBB expression with lower overall survival. HBB expression increases breast cancer cells aggressiveness and associates with poor prognosis, pointing to HBB as a novel biomarker for breast cancer progression.

// Giovanni Luca Gravina 1, 2 , Andrea Mancini 2 , Claudia Mattei 3 , Flora Vitale 3 , Francesco Marampon 2 , Alessandro Colapietro 2 , Giulia Rossi 2 , Luca Ventura 3 , Antonella Vetuschi 4 , Ernesto Di Cesare 1 , Judith A. Fox 5 , Claudio Festuccia 2 1 Department of Biotechnological and Applied Clinical Sciences, Division of Radiotherapy, University of L’Aquila, L’Aquila, Italy 2 Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L’Aquila, L’Aquila, Italy 3 Department of Biotechnological and Applied Clinical Sciences, Laboratory of Neurosciences, University of L’Aquila, L’Aquila, Italy 4 Department of Biotechnological and Applied Clinical Sciences, Chair of Human Anatomy, University of L’Aquila, L’Aquila, Italy 5 Sunesis Pharmaceuticals Inc., South San Francisco, CA, USA Correspondence to: Claudio Festuccia, email: claudio.festuccia@univaq.it Keywords: glioblastoma, topoisomerase II, vosaroxin, double-strand breaks, radiotherapy Received: December 14, 2016 Accepted: March 03, 2017 Published: March 13, 2017 ABSTRACT Purpose: Glioblastoma multiforme (GBM) is the most aggressive brain tumor. The activity of vosaroxin, a first-in-class anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II, was investigated in GBM preclinical models as a single agent and combined with radiotherapy (RT). Results: Vosaroxin showed antitumor activity in clonogenic survival assays, with IC 50 of 10−100 nM, and demonstrated radiosensitization. Combined treatments exhibited significantly higher γH2Ax levels compared with controls. In xenograft models, vosaroxin reduced tumor growth and showed enhanced activity with RT; vosaroxin/RT combined was more effective than temozolomide/RT. Vosaroxin/RT triggered rapid and massive cell death with characteristics of necrosis. A minor proportion of treated cells underwent caspase-dependent apoptosis, in agreement with in vitro results. Vosaroxin/RT inhibited RT-induced autophagy, increasing necrosis. This was associated with increased recruitment of granulocytes, monocytes, and undifferentiated bone marrow–derived lymphoid cells. Pharmacokinetic analyses revealed adequate blood-brain penetration of vosaroxin. Vosaroxin/RT increased disease-free survival (DFS) and overall survival (OS) significantly compared with RT, vosaroxin alone, temozolomide, and temozolomide/RT in the U251-luciferase orthotopic model. Materials and Methods: Cellular, molecular, and antiproliferative effects of vosaroxin alone or combined with RT were evaluated in 13 GBM cell lines. Tumor growth delay was determined in U87MG, U251, and T98G xenograft mouse models. (DFS) and (OS) were assessed in orthotopic intrabrain models using luciferase-transfected U251 cells by bioluminescence and magnetic resonance imaging. Conclusions: Vosaroxin demonstrated significant activity in vitro and in vivo in GBM models, and showed additive/synergistic activity when combined with RT in O6-methylguanine methyltransferase-negative and -positive cell lines.

(hbd) PRELP is a peptide corresponding to the N-terminal heparin binding domain of the matrix protein proline/arginine-rich end leucine-rich repeat protein (PRELP). (hbd) PRELP inhibits osteoclastogenesis entering pre-fusion osteoclasts through a chondroitin sulfate- and annexin 2-dependent mechanism and reducing the nuclear factor-κB transcription factor activity. In this work, we hypothesized that (hbd) PRELP could have a pharmacological relevance, counteracting bone loss in a variety of in vivo models of bone diseases induced by exacerbated osteoclast activity. In healthy mice, we demonstrated that the peptide targeted the bone and increased trabecular bone mass over basal level. In mice treated with retinoic acid to induce an acute increase of osteoclast formation, the peptide consistently antagonized osteoclastogenesis and prevented the increase of the serum levels of the osteoclast-specific marker tartrate-resistant acid phosphatase. In ovariectomized mice, in which osteoclast activity was chronically enhanced by estrogen deficiency, (hbd) PRELP counteracted exacerbated osteoclast activity and bone loss. In mice carrying osteolytic bone metastases, in which osteoclastogenesis and bone resorption were enhanced by tumor cell-derived factors, (hbd) PRELP reduced the incidence of osteolytic lesions, both preventively and curatively, with mechanisms involving impaired tumor cell homing to bone and tumor growth in the bone microenvironment. Interestingly, in tumor-bearing mice, (hbd) PRELP also inhibited breast tumor growth in orthotopic sites and development of metastatic disease in visceral organs, reducing cachexia and improving survival especially when administered preventively. (hbd) PRELP was retained in the tumor tissue and appeared to affect tumor growth by interacting with the microenvironment rather than by directly affecting the tumor cells. Because safety studies and high-dose treatments revealed no adverse effects, (hbd) PRELP could be employed as a novel biological agent to combat experimentally induced bone loss and breast cancer metastases, with a potential translational impact.

Purpose To search for a possible role of Peroxisome Proliferator-Activated Receptor α (PPARα), a molecular partner of the Aryl hydrocarbon receptor Interacting Protein (AIP), in somatotropinomas. Methods Tumours from 51 acromegalic patients were characterized for PPARα and AIP expression by immunohistochemistry (IHC) and/or Real Time RT-PCR. Data were analysed according to tumour characteristics and pre-operative treatment with somatostatin analogues (SSA). The effects of fenofibrate were studied in GH 3 cells in vitro . Results PPARα was expressed in most somatotropinomas. A modest relationship was found between PPARα and AIP expression, both being significantly higher in the presence of pre-operative SSA. However, only AIP expression was influenced by the response to treatment. Dual effects of fenofibrate were observed in GH 3 cells, consisting of cell growth inhibition and an increase in GH secretion inhibited by octreotide. Conclusions PPARα is a new player in somatotropinomas. Potential interactions between PPARα agonists and SSA may deserve further investigation.

In about 70% of patients affected by autosomal dominant osteopetrosis type 2 (ADO2), osteoclast activity is reduced by heterozygous mutations of the CLCN7 gene, encoding the ClC-7 chloride/hydrogen antiporter. CLCN7(G215R)-, CLCN7(R767W)-, and CLCN7(R286W)-specific siRNAs silenced transfected mutant mRNA/EGFP in HEK293 cells, in RAW264.7 cells and in human osteoclasts, with no change of CLCN7(WT) mRNA and no effect of scrambled siRNA on the mutant transcripts. Osteoclasts from Clcn7(G213R) ADO2 mice showed reduced bone resorption, a condition rescued by Clcn7(G213R)-specific siRNA. Treatment of ADO2 mice with Clcn7(G213R)-specific siRNA induced increase of bone resorption variables and decrease of trabecular bone mass, leading to an overall improvement of the osteopetrotic bone phenotype. Treatment did not induce overt adverse effects and was effective also with siRNAs specific for other mutants. These results demonstrate that a siRNA-based experimental treatment of ADO2 is feasible, and underscore a translational impact for future strategy to cure this therapeutically neglected form of osteopetrosis.

Background and aims Increased expression of Chromosome Region Maintenance (CRM-1)/exportin-1 (XPO-1) has been correlated with poor prognosis in several aggressive tumors, making it an interesting therapeutic target. Selective Inhibitor of Nuclear Export (SINE) compounds bind to XPO-1 and block its ability to export cargo proteins. Here, we investigated the effects of a new class of SINE compounds in models of prostate cancer. Material and methods We evaluated the expression of XPO-1 in human prostate cancer tissues and cell lines. Next, six SINE (KPT-127, KPT-185, KPT-205, KPT-225, KPT-251 and KPT-330) compounds having different potency with broad-spectrum, tumor-selective cytotoxicity, tolerability and pharmacokinetic profiles were tested in a panel of prostate cancer cells representing distinct differentiation/progression states of disease and genotypes. Two SINE candidates for clinical trials (KPT-251 and KPT-330) were also tested in vivo in three cell models of aggressive prostate cancer engrafted in male nude mice. Results and conclusions XPO-1 is overexpressed in prostate cancer compared to normal or hyperplastic tissues. Increased XPO-1 expression, mainly in the nuclear compartment, was associated with increased Gleason score and bone metastatic potential supporting the use of SINEs in advanced prostate cancer. SINE compounds inhibited proliferation and promoted apoptosis of tumor cells, but did not affect immortalized non-transformed prostate epithelial cells. Nuclei from SINE treated cells showed increased protein localization of XPO-1, survivin and cyclin D1 followed by degradation of these proteins leading to cell cycle arrest and apoptosis. Oral administration of KPT-251 and KPT-330 in PC3, DU145 and 22rv1 tumor-bearing nude mice reduced tumor cell proliferation, angiogenesis and induced apoptosis. Our results provide supportive evidence for the therapeutic use of SINE compounds in advanced/castration resistant prostate cancers and warrants further clinical investigation.

The authors describe the preliminary investigation of the natural mummies found in the church of the Holy Trinity in Popoli (inner Abruzzo region, Central Italy) and dating back from 1734 to 1845. The project was featuredas an episode in the National Geographic Channel series "The Mummy Road Show". The mummy of a male individual, 35-40 years old, underwent non-destructive examination with radiological, endoscopical, histological and X-ray diffraction analysis. The individual, belonging to high social class, was found affected by caries, paradontal disease, rib fractures, calcification of the diaphragm and renal urolythiasis. The recovery and complete investigation of the whole series of human remains will offer the opportunity to trace an anthropologic and paleopathologic profile of this interesting community.

Prostate cancer is the most common noncutaneous cancer among men in the United States. A genetic contribution to prostate cancer risk has been documented, but knowledge of the molecular mechanisms involved in prostate cancer initiation is still not well understood. Loss of heterozygosity (LOH) of chromosomal regions is crucial in tumor progression. In human prostate cancer, several chromosomal regions demonstrating a high frequency of LOH have been previously identified.KCTD11 (REN)is a tumor suppressor gene mapping on human chromosome 17p13.2, whose expression is frequently lost in human medulloblastoma and in several other cancer types. KCTD11 acts as a negative regulator of the Hedgehog (Hh) signaling. Here, we demonstrated thatKCTD11LOH is a common genetic lesion in human prostate adenocarcinoma. Indeed, nuclear KCTD11 protein expression is strongly reduced in primary prostate cancer, and this event correlated with overexpression of proteins acting into the Hedgehog pathway. Low levels ofKCTD11mRNA have been also observed in prostatic cancer cells, and ectopic overexpression of KCTD11 led to growth arrest. Our study demonstrates and supports that KCTD11, as well as negatively regulated downstream effectors belonging to Hh signaling, plays a role in prostate cancer pathogenesis. This could be suitable to characterize new diagnostic and therapeutic markers.

Background: Allergic rhinitis (AR) presents as the main and most invasive symptom in the blocking of the nose. This condition is almost always related to hypertrophy of the inferior turbinates. When the medical treatments are found to be insufficient to solve the obstructive symptom of the patient, the quality of life is considerably impaired and it is often necessary to submit the patient to a surgical approach. In the present study we aimed to establish the efficacy and safety of a new technique recently introduced for the shrinkage of hypertrophic turbinates using a specific device, based on a new radiofrequency energy that does not produce thermal mucosal damage, viz., quantic molecular resonance (QMR) in a group of patients with persistent moderate–severe allergic rhinitis, in addition to standard medical treatment (nasal steroid and oral antihistamine). Methods: All patients were randomly assigned to two homogeneous groups (group A, control subjects; group B, treated patients); each group included 145 individuals. During the study, both groups received standard medications (ebastine, 10-mg tablet, and budesonide nasal spray at 100 micrograms/nostril per day) for 90 days. Before the medical treatment, patients in group B underwent inferior endoscopic turbinoplasty using QMR. All of the patients enrolled in this study were submitted to a complete otorhinolaryngologic evaluation with objective clinical examination (basal rhinomanometry, nasal provocation test rhinomanometry, and mucociliary transport time), endoscopy, and questionnaires (22-item Sino-Nasal Outcome Test and visual analog scale for nasal symptoms). Results: Greater efficacy has been achieved using a combined approach with the association of medical and QMR treatment, compared with medical treatment alone, in the control of AR associated with hypertrophy of the inferior turbinates, in particular in the reduction of turbinate volume at rhinoendoscopy. Conclusion: QMR inferior turbinoplasty, in conjunction with medical therapy, improves the nasal flow, without any thermal mucosal damage, more effectively when compared with medical treatment alone in persistent moderate-to-severe AR. In particular, local reactivity, as measured with nasal provocation test, was noticeably reduced. (Am J Rhinol Allergy 28, 164–168, 2014; doi: 10.2500/ajra.2014.28.3990) A llergic rhinitis (AR) presents as the main and most invasive symptom in the blocking of the nose. This condition is almost always related to hypertrophy of the inferior turbinates, area of the immunophlogosis, which leads to persistent inflammation with edema and prolapse of the mucosa obstructing the nasal fossa. Hypertrophy of the inferior turbinate may become irreversible when the vascular dilatation leads to prolapse of the submucosal venous sinusoids, which no longer respond to the sympathetic system and to medical treatment.1,2 Several studies have revealed that a percentage (between 10 and 25%) of the population present nasal obstructive symptoms with hypertrophy of the inferior turbinates, correlated with the allergy.3 When the medical treatments (antihistamines, steroids, and specific immunotherapy) are found to be insufficient to solve the obstructive symptom of the patient, the quality of life (QoL) is considerably impaired and it is often necessary to submit the patient to a surgical approach to improve the nasal airflow.4 Surgery of the turbinates is, in fact, very common and represents the eighth procedure, in order of frequency, performed in otorhinolaryngologic surgery. Over the years, numerous surgical techniques have been proposed for the treatment of the inferior turbinate hypertrophy: the main problem was to increase the nasal airflow while maintaining the function of the mucosa, area of important protective actions, and of the absorption of medications useful in the long-term postoperative treatment of the allergic phlogosis (turbinectomy, submucosal emptying, cryocoagulation, electrocaustication, laser, radiofrequencies, and coblator).2,5,6 Many of these techniques (in particular those performed at high temperatures and extremely destructive, with almost complete amputation of the turbinate, despite the guarantee of an increase in the nasal airflow) were accompanied by the loss of nasal sensitivity and by the formation of such air vortex to the so-called “empty nose” syndromes with the formation of crusts, bleeding, and synechia, resulting in an extremely negative impact on the QoL of the patients.2,7–9 In the present study we aimed to establish the efficacy and safety of a new technique recently introduced for the shrinkage of hypertrophic turbinates using a specific device, based on a new radiofrequency energy that does not produce thermal damage, viz., quantic molecular resonance (QMR), in a group of patients with persistent moderate–severe AR, in addition to standard medical treatment (nasal steroid and oral antihistamine).10

Summary p27 Kip1 , a cyclin-dependent kinase inhibitor, is considered to be a tumor suppressor gene. Absent or reduced expression of the p27 Kip1 protein has been reported being a negative prognostic marker in primary lung, breast, colon, bladder, and prostate carcinomas. p27 Kip1 protein expression was evaluated in a series of 96 gastric carcinomas with no lymph node involvement (N0) to verify any impact on the clinical outcome. The analysis also considered the classic clinico-pathological parameters, such as age, sex, and depth of tumor invasion (pT). The most widely used classification systems for gastric carcinoma were adopted. The expression of p27 Kip1 was related neither to the pT category nor to tumor histology. Kaplan-Meier analysis documented a significant impact of an advanced pT category ( p Kip1 -reduced expression ( p Kip1 protein expression was a strong independent predictor of poor outcome, ranking second to the pT category only (p Kip1 appears to be associated with the clinical outcome of gastric carcinoma.

Estrogen receptor (ER) analysis was performed in 46 primary breast carcinomas using four monoclonal antibodies (MABs) to ER (AER311, ER1D5, LH1, and LH2), each of which recognizes a distinct domain of the receptor protein. ER was expressed as the percentage of positively stained tumor cells. Statistical analysis was performed using the SPSS/PC+ program to set the cut off of positivity and the prognostic value of each MAB. A positivity >30% for each MAB possessed the best sensitivity/specificity ratio and was used as the cut-off value. Multivariate discriminant analysis showed that MABs AER311, ER1D5, and LH2 had significant prognostic value. Fourteen tumors showed positivity for these three MABs; 17 were positive for one or two of the three MABs, and 15 were negative for all three MABs. Survival analysis showed that patients with tumors negative for all three of these MABs had progression of the disease within 8 years from the diagnosis of the tumor, whereas all patients with tumors positive for all three MABs were alive 13 years after surgery. A significant correlation (P = 0.0006) between tumor grading and ER status was found; 71% of the tumors that were positive for all three MABs were grade 1, whereas tumors negative for all three MABs were mostly grades 2 and 3. No significant relationship was observed between ER status and tumor size. A significant correlation (P = 0.008) between lymph node status and ER was found; breast tumors positive for all three MABs were in the majority (92.9%) of cases pNO, whereas 67% of tumors negative for all three MABs were pN1. Results from the present study suggest that the use of a panel of MABs that target distinct epitopes within domains of the ER protein could offer a better approach for assessing the ER status in breast cancer patients, because it enables the recognition of breast tumors with intact or structurally defective ER proteins.

BACKGROUND p27Kip1 is a cyclin-dependent kinase inhibitor and is a potential tumor suppressor gene. Reduced expression of p27Kip1 is a powerful negative prognostic marker in primary lung, breast, colon, bladder, and prostate carcinomas. In the current study, the prognostic value of p27Kip1 in gastric cancer was evaluated and compared with other histopathologic parameters and p53 expression. METHODS p27Kip1 and p53 protein expression were determined by immunohistochemistry in 96 gastric carcinomas. The tumors were from a low incidence population and were selected for the absence of lymph node involvement. RESULTS Reduced expression of p27Kip1 (≤ 50% positive cells) and nuclear p53 accumulation (> 30% positive cells) were observed in 67 (69.8%) and 9 (9%) tumors, respectively, and were not related to either the pT category or tumor histology. Kaplan–Meier analyses revealed a significant impact on survival by p27Kip1 (P = 0.0001 by log rank test), p53 (P < 0.0001) expression, and the pT category (P < 0.0001). On multivariate analysis, reduced p27Kip1 protein expression was the strongest independent predictor of reduced survival (P = 0.005; relative risk = 3.348) out weighing the pT category (P = 0.010; relative risk = 2.257) and p53 overexpression (P = 0.016; relative risk = 2.618). CONCLUSIONS These data indicated that immunohistochemical detection of p27Kip1 could help to identify gastric carcinoma patients who are at high risk of death, even in the absence of lymph node involvement, and who might benefit from an adjuvant treatment following surgery. Cancer 2000;89:2247–57. © 2000 American Cancer Society.

A 38-year-old woman with extensive hemorrhagic endometriosis causing back pain, pelvic masses, and hydronephrosis also had a palpable omental mass composed of abundant endometrial-type stroma in which the epithelial component was entirely tubal type glandular cells; the stroma in this area did not bleed. This difference in bleeding behavior supports the concept that patterns of differentiation of heterotopic müllerian tissues may depend in part on the influence of local factors and that endometrial epithelium may produce a local trophic or paracrine factor that is absent in tubal epithelium.