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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.

Giacomo Torno was born in 1539 (or 1541) in Naples. At the age of 18 he joined the Clerics Regular Theatines in San Paolo Maggiore and was welcomed on 30 October 1558. He suffered a stroke on 4 December 1608 and died 45 days later. Contemporary sources report that he appeared to be tormented by the devil during his illness, suffering from constant spasms in his arm, which caused him great discomfort. During the analysis of his mummified body, a discontinuity of the skin surface at the level of the sacrum was discovered. All morphological features indicate a wound that developed during the subject's life. Based on historical sources, the fracture of the first coccygeal vertebra, the appearance of the lesion near death, and the shape of the lesion, suggest that this is the first recorded instance of the Kennedy terminal ulcer, identified through both direct and indirect sources. [ABSTRACT FROM AUTHOR]

During the canonical recognition of Jean Bassand's partially skeletonized mummy, digital X-ray examination and computed tomography scanning revealed the presence of 5 coins from Italian mints (15th-16th century). The coins were recovered endoscopically: in the pelvis 3 quattrini of the Republic of Florence (one of which with signs of withdrawal from circulation) dating after 1472, and 1 cavallo of Aquila coined under Charles VIII of Valois (1495-1496); in the skull 1 quattrino of Pier Luigi Farnese, duke of Castro (1537-1545). These items, possibly survived from a richer deposit, may represent part of the offerings, which have become chronological indicators of ceremonies (50th and 100th anniversaries). Probably, they were intentionally repositioned during further inspections following earthquakes (1703) or desecrations (1529, 1799). The study aims to establish the period of production and free flow - in the Aquila's area - of these coins, in order to determine possible historiographical relationships with the body. [ABSTRACT FROM AUTHOR]

Brucellosis is a disease caused by the bacterium Brucella and typically transmitted through contact with infected ruminants. It is one of the most common chronic zoonotic diseases and of particular interest to public health agencies. Despite its well-known transmission history and characteristic symptoms, we lack a more complete understanding of the evolutionary history of its best-known species—Brucella melitensis. To address this knowledge gap we fortuitously found, sequenced and assembled a high-quality ancient B. melitensis draft genome from the kidney stone of a 14th-century Italian friar. The ancient strain contained fewer core genes than modern B. melitensis isolates, carried a complete complement of virulence genes, and did not contain any indication of significant antimicrobial resistances. The ancient B. melitensis genome fell as a basal sister lineage to a subgroup of B. melitensis strains within the Western Mediterranean phylogenetic group, with a short branch length indicative of its earlier sampling time, along with a similar gene content. By calibrating the molecular clock we suggest that the speciation event between B. melitensis and B. abortus is contemporaneous with the estimated time frame for the domestication of both sheep and goats. These results confirm the existence of the Western Mediterranean clade as a separate group in the 14th CE and suggest that its divergence was due to human and ruminant co-migration. Author summary: We describe the reconstruction of a high-quality ancient B. melitensis genome isolated from the kidney stone of a 14th C. CE Italian friar. We confirm the presence of a B. melitensis genome from the Western Mediterranean clade in Italy during this time period and refine previous estimates for the diversification of this phylogenetic group. In addition, we propose that the speciation event separating B. abortus and B. melitensis occurred during the domestication of sheep and goats approximately 9000 BCE. By comparing the gene content of the ancient B. melitensis genome with modern isolates, we provide evidence that neither the B. melitensis phylogenetic groups nor their respective sequence types necessarily correspond with the genetic components of their strains. The accessory genome of B. melitensis appears to be influenced by its geographic location, more so than its sequence type. We propose splitting the Eastern Mediterranean clade into three smaller groups to better reflect these genomic differences. [ABSTRACT FROM AUTHOR]

Copyright of Collegium Antropologicum is the property of Croatian Anthropological Society and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

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. [ABSTRACT FROM AUTHOR]

Copyright of Collegium Antropologicum is the property of Croatian Anthropological Society and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objectives: We report an ancient case of bilateral fabella, diagnosed in the mummified body of the Blessed Jean Bassand, dating back to the 15th century. Materials and Methods: The mummy belonged to an elderly subject and underwent canonical recognition by external inspection, digital radioscopic and X‐ray examination and computed tomography (CT) scanning. Results: Plain films, CT scans and visual inspection displayed two bilateral, discrete, rounded osseous structures with regular cortical profile, projecting in the posterosuperior aspect of the lateral femoral condyles. Based on the location and anatomical features, the structures were identified as fabellae. Discussion: To the best of our knowledge, this case represents the first description of fabella in ancient human remains, as well as the most ancient documented report of this sesamoid bone in human history, dating back the condition to the 15th century. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Advanced morphological and analytical methods play a very important role in paleopathological investigation. Depending on the availability of the instruments, a modern pathologist should be prepared to choose the most suitable technique to the specific question and be able to interpret the results obtained. The aim of this paper is to illustrate the application of such methods through a series of practical examples dating back from Egyptian dynastic to contemporary mummified tissues, in order to outline a basic guideline for paleopathologists in different settings. [ABSTRACT FROM AUTHOR]

Metastatic castration resistant prostate cancer (mCRPC) relapses due to acquired resistance to docetaxel-based chemotherapy and remains a major threat to patient survival. In this report, we tested the effectiveness of a dual CXCR4/E-selectin antagonist, GM-I1359, in vitro and in vivo, as a single agent or in combination with docetaxel (DTX). This agent was compared to the single CXCR4 antagonist, CTCE-9908, and E-selectin antagonist, GMI-1271. Here we demonstrate that CXCR4 antagonism reduced growth and enhanced DTX treatment in PCa cell lines as well as restored DTX effectiveness in DTX-resistant cell models. The efficacy of dual antagonist was higher respect to those observed for single CXCR4 antagonism. GM1359 impacted bone marrow colonization and growth in intraventricular and intratibial cell injection models. The anti-proliferative effects of GMI-1359 and DTX correlated with decreased size, osteolysis and serum levels of both mTRAP and type I collagen fragment (CTX) in intra-osseous tumours suggesting that the dual CXCR4/E-selectin antagonist was a docetaxel-sensitizing agent for bone metastatic growth. Single agent CXCR4 (CTCE-9908) and E-selectin (GMI-1271) antagonists resulted in lower sensitizing effects compared to GMI-1359. These data provide a biologic rationale for the use of a dual E-selectin/CXCR4 inhibitor as an adjuvant to taxane-based chemotherapy in men with mCRPC to prevent and reduce bone metastases. [ABSTRACT FROM AUTHOR]

In the article, the authors feature Italian polyhistor Antonio Ludovico Antinori (1704-1778) and his diagnosis of polymyalgia rheumatica (PMR) by his friend and personal doctor Venanzio Lupacchini (1730-1775) to show that the disease occurred in past times. Also cited are the symptoms of PMR like acute or subacute pain and stiffness in the neck, upper arms, thighs, and hips, as well as the link of PMR with giant cell arteritis (GCA).

Peroxisome proliferator-activated receptor alpha (PPARa) 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 PPARa in additional phenotypes of pituitary adenomas (PA), the relationship between PPARa and its potential molecular partner aryl hydrocarbon receptor interacting protein (AIP) in these tumours, and the effects of PPARa agonists on lactotroph cells. Seventy-five human PA - 57 non-functioning (NFPA) and 18 prolactinomas (PRL-PA) - were characterised for PPARa 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. PPARa was expressed in a majority of PA. PPARa 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). PPARa 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, PPARa is commonly expressed by PRL-PA and NFPA, regardless of AIP, and may represent a new target of PPARa agonists. [ABSTRACT FROM AUTHOR]

Background: Besides its role as oxygen transporter, recent findings suggest that haemoglobin beta (HBB) may have roles in other contexts.Methods: 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.Results: 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.Conclusions: HBB expression increases breast cancer cells aggressiveness and associates with poor prognosis, pointing to HBB as a novel biomarker for breast cancer progression. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 that KCTD11 LOH 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 of KCTD11 mRNA 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 downstreameffectors belonging to Hh signaling, plays a role in prostate cancer pathogenesis. This could be suitable to characterize new diagnostic and therapeutic markers. [ABSTRACT FROM AUTHOR]

ABSTRACT hbdPRELP is a peptide corresponding to the N-terminal heparin binding domain of the matrix protein proline/arginine-rich end leucine-rich repeat protein (PRELP). hbdPRELP 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 hbdPRELP 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, hbdPRELP 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, hbdPRELP 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, hbdPRELP 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. hbdPRELP 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, hbdPRELP could be employed as a novel biological agent to combat experimentally induced bone loss and breast cancer metastases, with a potential translational impact. [ABSTRACT FROM AUTHOR]

Bone is the preferential site of distant metastasis in breast carcinoma (BrCa). Patients with metastasis restricted to bone (BO) usually show a longer overall survival compared to patients who rapidly develop multiple metastases also involving liver and lung. Hence, molecular predisposition to generate bone and visceral metastases (BV) represents a clear indication of poor clinical outcome. We performed microarray analysis with two different chip platforms, Affymetrix and Agilent, on bone metastasis samples from BO and BV patients. The unsupervised hierarchical clustering of the resulting transcriptomes correlated with the clinical progression, segregating the BO from the BV profiles. Matching the twofold significantly regulated genes from Affymetrix and Agilent chips resulted in a 15-gene signature with 13 upregulated and two downregulated genes in BV versus BO bone metastasis samples. In order to validate the resulting signature, we isolated different MDA-MB-231 clonal subpopulations that metastasize only in the bone (MDA-BO) or in bone and visceral tissues (MDA-BV). Six of the signature genes were also significantly upregulated in MDA-BV compared to MDA-BO clones. A group of upregulated genes, including Hemoglobin B ( HBB), were involved in oxygen metabolism, and in vitro functional analysis of HBB revealed that its expression in the MDA subpopulations was associated with a reduced production of hydrogen peroxide. Expression of HBB was detected in primary BrCa tissue but not in normal breast epithelial cells. Metastatic lymph nodes were frequently more positive for HBB compared to the corresponding primary tumors, whereas BO metastases had a lower expression than BV metastases, suggesting a positive correlation between HBB and ability of bone metastasis to rapidly spread to other organs. We propose that HBB, along with other genes involved in oxygen metabolism, confers a more aggressive metastatic phenotype in BrCa cells disseminated to bone. © 2012 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

During an excavation campaign in the Church of the Conversion of Saint Paul in Roccapelago (North Italy), a hidden crypt was discovered, which yielded the remains of more than 400 individuals. The crypt was used as a cemetery by the inhabitants of the village of Roccapelago between the 16th and 18th centuries. Along the north side of the crypt, an area apparently separated from the rest of the burials was found, bordered by stones, where several burials of newborns and infants were concentrated. From here, five fabric rolls containing bones were recovered, and it was decided not to carry out destructive analyses, allocating the two best examples to a thorough radiological investigation to try to define the type of burial and the complete biological profile of the infant. The two rolls, subjects of this study, can be dated archaeologically between the 17th and 18th centuries. CT analysis shows a varied group of bones with a fairly good state of conservation. The paleoradiological study carried out had the primary objective of avoiding the destruction of the two rolls, ensuring their conservation; but at the same time, providing essential data to understand their nature, defining the biological profile and the type of deposition. [ABSTRACT FROM AUTHOR]