Survival analysis of the metastatic cohort of Italian Association of Medical Oncology (AIOM) GARIBALDI survey.

This analysis from the GARIBALDI study was aimed to address the role of center self-declared expertise, type and commitment on the overall survival (OS) of patients with metastatic Pancreatic Ductal Adenocarcinoma (mPDAC). Treatment-naïve patients ≥18-year with pathological diagnosis of mPDAC were enrolled. OS was defined as the time from chemotherapy start to death from any cause. The impact of clinical-demographic and centers characteristics on OS was evaluated using Cox models. Between July 2017 and October 2019, 473 patients enrolled in 43 centers were eligible for this analysis. Median age was 69.3 (first-third quartile 61.2-74.5); 46.1 % females; 90.8 % ECOG PS 0-1; 67.4 % had liver metastases; median CA19.9700.5 UI/mL (first-third quartile 77.5-6629.5). For 37.1 % of patients chemotherapy started <4 weeks from diagnosis; 69.9 % of patients received nab-paclitaxel + gemcitabine; 16.9 % gemcitabine alone; 7.6 % FOLFIRINOX. The median follow-up was 51.8 months and 428 patients died. No statistically significant role of the type of institution was observed. Additionally, no statistically significant role of neither the self-declared expertise nor the accrual rate was observed. The GARIBALDI study suggests that the self-declared center expertise and the academic brand are not associated to OS in patients with mPDAC, while center commitment warrants further exploration.

Preserving the Aromatic Profile of Aged Toma Piemontese PDO Cheese with Gaseous Ozone Technology: A Quality Assessment via SPME-GC-MS/E-Nose.

The efficacy of low gaseous ozone concentrations (300 ppb and 400 ppb) in controlling spoilage microflora and preserving the quality of the aged Toma Piemontese PDO cheese was explored. The research integrates consumer tests, Gas Chromatography-Mass Spectrometry (GC-MS) with Solid phase Microextraction (SPME) fiber and Electronic Nose (e-nose) analysis to conduct a detailed assessment of the cheese's aromatic composition. Results indicate that low ozone concentrations significantly affected spoilage microflora, preserving the overall quality. Through GC-FID (Flame Ionization Detection) analysis, 22 of all identified compounds by GC-MS were quantified, including ethyl acetate (sweety), diacetyl and acetoin (buttery). Compared with the untreated sample, ozone treatments maintained the distinctive characteristics of Toma Piemontese PDO cheese, reducing the formation of off-flavors-related compounds (i.e., ethanol). Moreover, ozone-treated samples correlated with positive aroma scores given by consumers. However, sensory perception involves complex interactions among aroma compounds, highlighting the importance of advanced approaches. The utilization of a 12-sensor Quartz Microbalance (QMB) e-nose played a crucial role in identifying subtle differences in aroma, contributing to a more nuanced understanding of ozone treatments on the cheese's sensory profile. In conclusion, this research demonstrates the potential of ozone technology as a viable and effective method for improving the quality of aged Toma Piemontese PDO cheese.

Psychopathological symptoms and their association with the quality of life and the sexual functioning in women affected by systemic scleroderma: a preliminary investigation.

OBJECTIVE: This study aimed to investigate the presence of psychopathological symptoms and the relations of these dimensions with the quality of life and sexual function in a group of women affected by systemic scleroderma. SUBJECTS AND METHODS: Seventy-one women with systemic scleroderma were invited to participate in the study; 65 agreed to participate, while 6 declined. Four questionnaires were administered to the patients: a specific socio-demographic questionnaire, the Symptom Checklist-90-Revised (SCL-90-R), the Female Sexual Function Index (FSFI), and the Quality-of-Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO-41). RESULTS: Of all the participants in this study, 48% of patients showed a clinical score on SCL-90-R Somatization, 45% on depression, and 37% on obsessive-compulsive. As hypothesized, psychopathological symptoms were related to lower quality of life since somatization and depression predicted the total score of health-related quality of life and lower sexual functions, showing a specific effect of depression on sexuality. CONCLUSIONS: Our findings highlighted the presence of an association between psychopathological symptoms and reduced sexual functioning and the associations between somatization and the health-related quality of life dimensions in scleroderma patients. Furthermore, our results sustain the importance of also considering the mental health of patients with systemic sclerosis, within an integrated biopsychosocial care model.

Effect of the BRCA2 CTRD domain on RAD51 filaments analyzed by an ensemble of single molecule techniques.

Homologous recombination is essential for the preservation of genome stability, thereby preventing cancer. The recombination protein RAD51 drives DNA strand exchange, which requires the assembly, rearrangement and disassembly of a RAD51 filament on DNA, coupled to ATP binding and hydrolysis. This process is facilitated and controlled by recombination mediators and accessory factors. Here, we have employed a range of single molecule techniques to determine the influence of the C-terminal RAD51 interaction domain (CTRD) of the breast cancer tumor suppressor BRCA2 on intrinsic aspects of RAD51-DNA interactions. We show that at high concentration the CTRD entangles RAD51 filaments and reduces RAD51 filament formation in a concentration dependent manner. It does not affect the rate of filament disassembly measured as the loss of fluorescent signal due to intrinsic RAD51 protein dissociation from double-stranded DNA (dsDNA). We conclude that, outside the context of the full-length protein, the CTRD does not reduce RAD51 dissociation kinetics, but instead hinders filament formation on dsDNA. The CTRDs mode of action is most likely sequestration of multiple RAD51 molecules thereby rendering them inactive for filament formation on dsDNA.

Fatigue in Sjogren's syndrome: relationship with fibromyalgia, clinical and biologic features.

More than two third of patients with primary Sjögren's syndrome (SS) report fatigue. Despite its clinical relevance, only a few studies have examined the relationship of fatigue with the presence of an overlapping Fibromyalgia (FM) and other clinical and biological variables. The aim of this study was to assess the relationship between fatigue and SS disease activity and damage, FM, widespread pain, and mood disorders; finally, the possible correlation between fatigue and a panel of cytokines likely to drive the immunopathological process of the disease has been examined. Thirty-five female patients with primary SS were consecutively enrolled; for each patient the Sjögren's Syndrome Disease Damage Index (SSDDI) and the Sjögren's Syndrome Disease Activity Index (SSDAI) were calculated. Patients rated pain, fatigue and disease activity using a 100-mm VAS and completed Health Assessment Questionnaire (HAQ), the Zung depression (ZSDS) and anxiety scales (ZSAS). 30/35 patients (85.7%) felt unduly tired and the same percentage of patients suffered with pain in more than one area of the body. 7 patients satisfied ACR criteria for FM, representing 20% of the whole cohort and 23% of SS patients with fatigue. No differences were found in disease duration, SSDDI, SSDAI, ZSDS and ZSAS among SS patient with or without FM. In the whole group, fatigue VAS correlated with HAQ, ZSAS, ZSDS and pain VAS but not with age, disease duration, presence and severity of arthritis, SSDDI, SSDAI, or cytokines. In conclusion, an overlapping FM can contribute to, but does not entirely account for fatigue in Italian patients with primary SS.

Exploratory data analysis on the effects of non pharmacological treatment for knee osteoarthritis.

OBJECTIVES: Osteoarthritis (OA) is a chronic rheumatic disease characterized by progressive cartilage destruction mediated by cytokines and other molecules. Chondrocyte activity and metabolism have attracted interest as targets of drug intervention, and spa-therapy can influence the serum levels of several cytokines. We investigated the effects of spa-therapy on clinical and ultrasonographic (US) findings and serum levels of cartilage oligomeric matrix protein (COMP) and several cytokines, chemokines, and growth factors in a prospective cohort of patients with symptomatic knee OA. METHODS: Patients (n=53) with primary symptomatic knee OA were treated for 12 consecutive days with locally applied mud-packs. Assessments were made at baseline, immediately after completion of the treatment cycle, and 6 and 12 months after completion of treatment. They included visual analogue scale (VAS) ratings of pain, the Lequesne algofunctional index for knee OA, and US with calculation of a semiquantitative score that expressed the severity of the local inflammatory process. Serum levels of 27 cytokines (including interferon--inducible protein-10 [IP-10]), chemokines, and growth factors were measured with multiplex bead-based immunoassays, and COMP levels were determined by ELISA. RESULTS: US scores, VAS pain ratings, and Lequesne indexes indicated significant improvement after spa-therapy and at the 6- and 12-month follow-ups. Serum IP-10 levels also dropped significantly (p=0.0035), and this reduction was positively correlated with improvement of the Lequesne index (p=0.031). CONCLUSIONS: In patients with knee OA, spa-therapy can modulate serum levels of proinflammatory cytokines/chemokines and produce improvements in joint pain and function that persists for up to 1 year.

DNA repair: spot(light)s on chromatin.

Chromatin modifications regulate many nuclear processes. Recent studies on the phosphorylation of a histone 2A variant have revealed that this chromatin modification is a general and evolutionarily conserved cellular response to DNA double-strand breaks.

Immunity to extracellular matrix antigens is associated with ultrastructural alterations of the stroma and stratified epithelium basement membrane in the skin of Hashimotos thyroiditis patients.

Employing purified extracellular matrix (ECM) proteins, i.e. type I, III, IV and V collagens (CI, CIII, CIV, CV), laminin (LM) and fibronectin (FN), as antigen sources we detected autoantibodies to conformational and/or denatured ECM antigens among 34 of 50 sera obtained from Hashimotos thyroiditis (HT) patients and 6 of 51 control sera obtained from non-autoimmune thyroid disease patients and healthy donors (HT sera vs. control sera p=4 x 10-9). Reactivity to conformational antigens, mostly due to autoantibodies of the IgG isotype, was observed in 30/50 HT sera and in 6/51 control sera (p=3.5 x 10-7) and was not always concomitant with that to linear antigens, found in 23/50 HT and in 6/51 control sera (p=1.6 x 10-4). Ultrastructural analysis of skin biopsies obtained from 18 HT patients without symptomatic cutaneous diseases revealed defects of the stratified squamous epithelium basement membrane in 11/18, alterations of the stroma in 13/18 and both basement membrane and stromal defects in 9/18. Interestingly, 13/13 (p=0.012) and 9/11 (p=0.012) patients with stromal and basement membrane defects respectively, exhibited serum antibodies to at least one ECM antigen involved in the organization of the altered tissue compartment. Lastly, 10/18 skin biopsies presented immunoglobulin (Ig) and/or complement (C3) deposits along the cutaneous basement membrane zone (BMZ) or in the papillary dermis and 9/10 sera from the same patients simultaneously showed antibodies to at least one ECM antigen involved in the organization of these two skin compartments. Besides, 8/11 HT patients with basement membrane defects exhibited Ig or C3 deposits along the BMZ. Our findings suggest that autoantibodies to ECM molecules might contribute to the development of asymptomatic extra-thyroid skin diseases in HT patients.

DNA-binding and strand-annealing activities of human Mre11: implications for its roles in DNA double-strand break repair pathways.

DNA double-strand breaks (DSBs) in eukaryotic cells can be repaired by non-homologous end-joining or homologous recombination. The complex containing the Mre11, Rad50 and Nbs1 proteins has been implicated in both DSB repair pathways, even though they are mechanistically different. To get a better understanding of the properties of the human Mre11 (hMre11) protein, we investigated some of its biochemical activities. We found that hMre11 binds both double- and single-stranded (ss)DNA, with a preference for ssDNA. hMre11 does not require DNA ends for efficient binding. Interestingly, hMre11 mediates the annealing of complementary ssDNA molecules. In contrast to the annealing activity of the homologous recombination protein hRad52, the activity of hMre11 is abrogated by the ssDNA binding protein hRPA. We discuss the possible implications of the results for the role(s) of hMre11 in both DSB repair pathways.

Role of extracellular matrix in regulation of staurosporine-induced apoptosis in breast cancer cells.

Autocrine and paracrine mechanisms modulate the synthesis and secretion of extracellular matrix (ECM); moreover, each component of the ECM is capable of modulating the synthesis and release of other ECM molecules. Therefore, the synthesis of ECM glycoprotein fibronectin and laminin was studied in the human breast cancer cell lines MCF7 and MDA MB 23, plated on different ECM. Our results showed that the cells plated on a fibronectin substrate increased laminin synthesis: this event correlated with an increase in alpha2 and alpha3 integrin subunits. Staurosporine-induced apoptosis was then analyzed in the cell lines plated on different ECM. Staurosporine treatment determined the apoptosis of 35 and 33% respectively of MDA MB 231 and MCF7; these values increased to 60 and 64% in cells plated on laminin, to 48 and 63% in cells plated on fibronectin and to 64 and 69% in cells plated on matrigel. Moreover, staurosporine treatment decreased bcl-2 expression in the cells plated on fibronectin and laminin. Yet, staurosporine treatment determined PARP cleavage and PARP partial disappearance when the cells were plated on matrigel. Finally, a partial loss of function mutant Ras protein that activated only Raf pathway, was expressed in MCF7, in order to identify whether the increase of apoptosis induced by extracellular matrix involved the Raf/MAP kinase pathway. The increase of apoptosis of the cells plated on matrigel suggested that the activation of the Raf pathway is probably involved in the decrease of survival on matrigel. These data demonstrate that the modification of ECM modulates the apoptotic process of breast cancer cells and suggest that it is worthwhile to dissect the role of ECM in the control of apoptotic process.

Reinforcing effect of organo-modified layered silicates in high-density polyethylene.

This study focuses on the understanding of the reinforcing effect given by organo-modified layered silicates to a high-density polyethylene and the influence on the crystallization properties of this polymer. The addition of organo-modified clay to high-density polyethylene resulted in an evident increase in the tensile and flexural Young's modulus of the material with respect to unfilled polymer. The morphology, crystallinity, and thermo-oxidative stability of such nanocomposites were investigated using X-ray diffraction, transmission electron microscopy, differential scanning calorimetry, and oxidation induction time test. The materials obtained show tactoid as well as intercalated and exfoliated structures with different dominant states depending on the loading level and process conditions. It was observed that organic ions not only change mixing behavior but also influence material properties, including the degree of crystallinity and the stability to the thermo-oxidative phenomena.

Immunosenescence and infectious diseases.

Infectious diseases are major causes, with malignancies, of morbidity and mortality in the elderly. Increased susceptibility to infections may result from underlying dysfunction of an aged immune system; moreover, inappropriate immunologic functions associated with aging can determine an insufficient response to vaccines. Impairments of cellular, humoral and innate immunity in the elderly, contributing to increased incidence of infectious diseases, are discussed in this review.

HTLV-I and HIV-1 infection in patients with lymphadenopathy syndrome detected during routine breast screening at a tumor prevention center.

Lymphadenopathy with no apparent cause had been reported in a group of women participating in a mammary tumor prevention program. A screening for retrovirus infection was organized to detect the virus as possible etiological agents. Data show a high percentage of positivity for HIV-1 among these lymphadenopathy patients, and surprisingly for HTLV-I, while no such positivity for either virus was found in matched controls or in patients where a different causal agent for lymphadenopathy was found. Of 26 seropositives, 23 deny any risk factor for HIV-1 and do not come from a HTLV-I known endemic area, but while it is impossible to exclude their knowledge of risk factors, it is worth noting that none of them presented a HTLV-I/HIV-1 double infection, which is very frequent in intravenous drug abusers, the major risk group in Italy. On the basis of these data spread of HTLV-I and HIV-1 appears to be more important in Italy than previously thought, and not confined to well-defined groups or, at least, among those who believe they do not belong to a risk group and therefore can represent a major vehicle for virus diffusion. Institution of screening for HTLV-I in blood donors should be taken immediately, and retrovirus infection risk criteria must be revised.

99mTc MIBI prone scintimammography in patients with suspicious breast cancer: relationship with mammography and tumor size.

99mTc MIBI prone scintimammography (PSM) is reported to be a specific examination in order to assess the nature of breast lesions. Fifty-three patients whose mammography was stratified according to the breast imaging reporting and data system (BI-RADS), the five category classification of mammography approved by the American college of radiology, were studied with prone scintimammography, with the aim of assessing the accuracy of this exam and its usefulness in clinical practice. Thirty-five out of forty-one patients with BI-RADS category V (high probability of cancer) showed cancer at histology. Thirty-one of them had positive PSM. Three out of the six patients with mammo-graphic features of category IV indicated malignancy. PSM was positive in all of them and negative in the three benign lesions. One of the five patients with category III mammography showed cancer and positive PSM. The PSM was negative in 12/13 patients with benign patology (specificity 92.3%). When the cancers were stratified for T-category significant differences were found between the sensitivity for tumors larger or smaller than 1 cm. The sensitivity was 50% for the cancers smaller than 1 cm and 96.9% for those larger than 1 cm. PSM is a very specific method to determine the nature of breast lesions. Its sensitivity is also high but has to be improved when tumors smaller than 1 cm have to be detected. From a clinical point of view PSM can at the moment be considered as an accurate method for the study of borderline lesions of IV and also of III BI-RADS category. In this case a positive PSM indicates an impact in clinical decision making.

Cytogenetic and interphase cytogenetic analyses reveal chromosome instability but no clonal trisomy 8 in Dupuytren contracture.

The results of cytogenetic and FISH analysis performed in 26 cases of Dupuytren contracture are reported. Clonal or sporadic chromosome changes were found in 18 cases (69%). Clonal changes consisted of: +2, +16, -10, -Y, add(1)(p23), del(2)(q21), t(3;16)(p21;q24), add (3)(p24), del(18)(q21), t(Y;14)(p12;q24), +mar. The results differ from those obtained in normal palmar fascia used as control, in which -Y and +Y were the only clonal changes found in 2 of 11 analyzed cases (18%). No clonal trisomy 8 was found. FISH analysis performed in 11 cases (centromeric probe specific for chromosome 8) failed to show the presence of a cell population with +8. Clonal and sporadic structural changes were different from case to case and no clustering breakpoint was observed. The significance of the chromosome instability leading to clonal and sporadic chromosome changes not specific to Dupuytren contracture are discussed.

99m Tc MIBI prone scintimammography in breast Paget's disease: a case report.

A 99m Tc MIBI prone scintimammography (PSM) was performed in a case of underlying Paget's disease of the breast. 99m Tc MIBI PSM showed a diffuse scintigraphic image like a spread of uptake from the deeply located zones of the breast toward epidermis. In vivo, 99m Tc MIBI PSM represents the spread of neoplastic Paget's cells probably attracted by chemotactic factors released by keratinocytes. This spread in Paget's disease is correlated to neu oncogene overexpression which increases the metastatic activity as a consequence of motility enhancement and growth stimulation effect. These scintigraphic images suggest that 99m Tc MIBI PSM could be relevant in management of Paget's disease of the breast.

Adhesion molecules on peripheral blood lymphocyte subpopulations in the elderly.

Adhesion molecules, such as CD49d, CD50 and CD62L, have important roles in many adhesive interactions involving cells of the immune system. Since it has been shown that many immunological alterations are present in aged subjects, we studied, by means of triple colour whole blood immunostaining and multiparametric flow cytometry, the expression and intensity level (MFI) of these molecules on peripheral blood lymphocyte subpopulations from 23 healthy elderly subjects and 13 young controls. In the elderly a decrease in total peripheral blood lymphocytes bearing CD62L antigen was observed (39 +/- 13% vs 63 +/- 6% and 745 +/- 312/mm3 vs 1,393 +/- 407/mm3; p<0.001), whereas the numbers of lymphocytes expressing CD49d and CD50 antigens were comparable in aged and young subjects. In addition, CD50 and CD62L MFI values on total peripheral blood lymphocytes were higher in elderly than in young subjects (5.23 +/- 1.03 vs 4.18 +/- 0.44, p = 0.001 and 2.60 +/- 0.35 vs 2.21 +/- 0.40, p = 0.005 respectively) while the intensity expression of CD49d was unchanged. The percentages and absolute numbers of T and B lymphocytes expressing CD62L were decreased in elderly compared to young subjects (CD62L+CD3+: 43 +/- 15% vs 66 +/- 9% and 581 +/- 257/mm3 vs 1,028 +/- 418/mm3, p<0.001; CD62L+CD19+: 78 +/- 12% vs 90 +/- 4%, p < 0.005 and 103 +/- 64/mm3 vs 207 +/- 98, p < 0.001). A decrease in the proportion of CD62L bearing NK cells was also observed in the elderly (25 +/- 14% vs 46 +/- 24%, p<0.005), although their absolute number was unchanged. No significant differences were detected in the proportion of T, B and NK lymphocytes expressing CD49d and CD50 antigens and only the absolute numbers of B cells expressing these adhesion molecules were lower in elderly (CD49d+CD19+: 121 +/- 71/mm3 and CD50+CD19+: 107 +/- 73/mm3) compared to young donors (CD49d+CD19+: 248 +/- 112/mm3 and CD50+CD19+: 235 +/- 120/mm3, p < 0.001). Moreover, the intensity of adhesion molecule expression was differentially modulated in the elderly depending on the specific lymphocyte cell population considered. The densities of CD49d, CD50 and CD62L antigens on B and NK lymphocytes from the two age groups were not different; on the contrary, T lymphocytes from elderly donors exhibited increased CD49d (1.69 +/- 0.09 vs 1.62 +/- 0.07, p < 0.05), CD50 (4.98 +/- 1.16 vs 3.77 +/- 0.46, p < 0.001) and CD62L (2.26 +/- 0.38 vs 1.99 +/- 0.37, p < 0.05) MFI values compared to young donors.

[Intra- and postoperative complications in surgery of the thyroid gland]. / Complicazioni intra- e post-operatorie nella chirurgia della tiroide.

The authors studied the inter- and postoperative complications arising in a series of 690 consecutive interventions on thyroid. The results showed a cipher mortality and a 3% aggregate morbidity. In 0.9% of cases, compressive hematomata in the thyroid loggia, collapse of the tracheal wall due to tracheomalacia or bilateral paralysis of the vocal cords determined an acute respiratory stoppage. 1.4% of the treated patients suffered from alterations in the motility of the vocal cords, ascribable to damage of the recurrent nerves. 0.9% of cases showed a postoperative parathyroid insufficiency, the nature of which, however, was always temporary. The incidence of complications, in the whole, resulted significantly higher in the patients undergoing iterative surgery, in respect of those operated on the first time.

[Blood coagulation changes and neoplastic pathology]. / Alterazioni emocagulative e patologia neoplastica.

Cancer patients show an increased susceptibility to develop thromboembolic diseases, suggesting that disorders of coagulation are very common in this pathology. Tumor cells possess the capacity to interact with the hemostatic system, activating the coagulation cascade and stimulating the prothrombotic properties of other blood cell components; the same events while inducing a hypercoagulable state, also contribute to the processes of tumor growth, neoangiogenesis and metastatic formation. Multiple risk factors associated with malignant disease contribute to the hypercoagulability state: stasis induced by prolonged bed rest, vascular invasion by the tumor and iatrogenic complications including the use of central vein catheters and chemotherapy. Several tests have been developed to assess the hypercoagulable state, however their clinical significance still needs to be defined, especially in terms of their predictive value for thrombosis. Clinical manifestations vary from localized deep venous thrombosis (DVT) or pulmonary embolism, more generally associated with solid tumors, to disseminated intravascular coagulation, frequent in hematologic malignancies and metastatic cancer. Diagnosis of idiopathic DVT, in the absence of other risk factors, could indicate the presence of occult cancer, but the usefulness of an extensive work-up to detect malignancy in terms of cost to benefit ratio still has to be demonstrated. Patients with cancer and thromboembolism must be treated with anticoagulant therapy; a large number of studies have shown that either low molecular weight heparins or standard unfractionated heparin for the treatment of acute deep vein thrombosis in hospitalized patients are equally safe and effective; however, the first treatment has been reported to be associated with a lower mortality. After an episode of thrombosis the patients should be protected by a long term course of oral anticoagulation, remaining high the risk of recurrence for as long as the cancer is active.