120 research outputs found
The xylanase inhibitor TAXI-III limits cell death induced by a xylanase secreted by Fusarium graminearum during wheat infection.
No full textCereals contain xylanase inhibitor proteins (XIs) which inhibit microbial xylanases from glycoside hydrolase families 10 and 11. In wheat, three types of XIs have been identified: Triticum aestivum XI (TAXI), xylanase inhibitor protein (XIP) and thaumatin-like XI (TLXI). These inhibitors are considered part of the defence mechanisms that plants use to counteract microbial pathogens and recently we provided in planta evidences for the protective role of TAXI-III, a member of the TAXI type XIs. To elucidate the molecular mechanism underlying the capacity of the transgenic plants expressing Taxi-III to limit Fusarium Head Blight (FHB) disease symptoms caused by F. graminearum, we performed infiltration experiments on wheat tissues with a xylanase strongly expressed by F. graminearum during wheat spike infection which we have previously demonstrated to induce cell death and hydrogen peroxide accumulation. Experiments performed on glumes of flowering wheat spikes showed that the presence of TAXI-III significantly decreased cell death and hydrogen peroxide accumulation. Most interestingly, similar results were also obtained by infiltrating the same xylanase on glumes of transgenic wheat plants expressing TAXI-III. These results suggest that the reduced FHB symptoms on transgenic TAXI-III plants can be due to the direct inhibition of xylanase activity secreted by the pathogen but also to the capacity of TAXI-III to prevent the recognition of xylanase by a plant receptor possibly involved in cell death elicitation
Spotlight on triptorelin in the treatment of premenopausal women with early-stage breast cancer
No full textMarta Venturelli,1 Giorgia Guaitoli,1 Claudia Omarini,1 Luca Moscetti2 1Division of Medical Oncology, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy; 2Division of Medical Oncology, Department of Oncology and Hematology, Azienda Ospedaliero Universitaria Policlinico di Modena, Modena, Italy Abstract: Endocrine treatment represents the cornerstone of endocrine-sensitive premenopausal early breast cancer. The estrogen blockade plays a leading role in the therapeutic management of hormone receptor-positive breast cancer together with surgery, radiotherapy, and selective antiestrogen treatments. For several years, selective estrogen receptor modulators, such as tamoxifen, have represented the mainstay of therapy. The role of amenorrhea has been extensively elucidated in the past year: the benefit observed with chemotherapy-induced amenorrhea has strengthened its therapeutic role. Luteinizing hormone-releasing hormone (LHRH) has been introduced in oncology practice to induce amenorrhea in order to increase the advantage obtained from endocrine treatment. Triptorelin is one of the most widely used LHRH analogs currently available in clinical practice. It was recently investigated in two major clinical trials that studied the role of complete estrogen blockade in the premenopausal setting. Both showed the clinical benefit due to ovarian suppression treatment, primarily in high-risk patients. Furthermore, triptorelin and other LHRH analogs have recently been investigated in the attempt to preserve the ovarian function in young patients. The medical treatment of early breast cancer is always evolving in the effort to search for safe and efficacious treatments. The role of LHRH analogs is actually well recognized as contributing to the improvement of the medical treatment of premenopausal women with early breast cancer. Keywords: adjuvant, hormone therapy, LHRH, amenorrhe
Overexpression of the xylanase inhibitor TAXI-III reduces Fusarium Head Blight symptom in durum wheat.
No full textXylanase inhibitor proteins (XIs) inhibit microbial xylanases from glycoside hydrolase
families 10 and 11. The wheat genome contains three types of XIs: Triticum aestivum XI (TAXI),
xylanase inhibitor protein (XIP) and thaumatin-like XI (TLXI). The genes encoding these inhibitors
may exist in multiple copies in the wheat genome and some of these are localized on chromosome
group 5. XIs are induced by pathogen infection and are responsive to wounding, jasmonic acid and
salicylic acid treatments. They are localized in the apoplastic region and are effective against
xylanases of microbial origin and not against endogenous plant xylanases. On the basis of these
features XIs are considered part of the defence mechanisms that plants use to counteract the activity
of xylanases secreted by microbial pathogens during infection. An additional aspect that reinforces
this possibility is the observation that xylaneses are important components during pathogenesis for
the fungal pathogens Botrytis cinerea and Septoria tritici.
In this report we focus our attention on TAXI-III, one member of the TAXI type XIs that have
been reported to be induced by Fusarium graminearum infection. The expression of the endogenous
Taxi-III is regulated in a tissue-specific manner, being expressed only in developing caryopsis and
roots. In order to facilitate the understanding of its contribution in wheat resistance, we expressed
Taxi-III under control of the constitutive maize Ubiquitin promoter. Results show that TAXI-III
accumulates in all tissues, including those that normally do not contain this inhibitor and its
presence endows the transgenic wheat with new inhibition capacities. We show also that the
transgene-encoded protein is correctly secreted into the apoplast and possesses the expected
inhibition properties against microbial xylanases. In particular, total protein wheat extract or
purified TAXI-III from transgenic plants fully inhibit a purified xylanase from Fusarium
graminearum and to some extent the total xylanase activity produced in vitro by this fungal
pathogen. These new inhibition properties of the transgenic tissues correlate with a significant
reduction of Fusarium Head Blight (FHB) disease symptom caused by F. graminearum.
In conclusion, our results provide for the first time specific evidences at the plant level that
XIs are involved in plant defence against fungal pathogens and show the possibility to manipulate
TAXI-III accumulation to improve wheat resistance against F. graminearum
Neoadjuvant treatments in triple-negative breast cancer patients: where we are now and where we are going
No full textAbstract: Triple-negative breast cancer (TNBC) remains the poorest-prognosis breast cancer
(BC) subtype. Gene expression profiling has identified at least six different triple-negative
subtypes with different biology and sensitivity to therapies. The heterogeneous nature of TN
tumors may justify the difficulty in treating this BC subtype. Several targeted agents have been
investigated in clinical trials without demonstrating a clear survival benefit. Therefore, systemic
chemotherapy remains the cornerstone of current clinical practice. Improving the knowledge of
tumor biology is mandatory for patient management. In stages II and III, neoadjuvant systemic
treatment is an effective option of care. The achievement of a pathological complete response
represents an optimal surrogate for survival outcome as well as a test for tumor drug sensitivity.
In this review, we provide a brief description of the main predictive biomarkers for tumor
response to systemic treatment. Moreover, we review the treatment strategies investigated for
TNBCs in neoadjuvant settings focusing on experimental drugs such as immunotherapy and
poly [ADP-ribose] polymerase inhibitors that hold promise in the treatment of this aggressive
disease. Therefore, the management of TNBC represents an urgent, current, unmet need in daily
clinical practice. A key recommendation is to design biology-driven clinical trials wherein TNBC
patients may be treated on the basis of tumor molecular profile
Durum wheat improvement against fungal pathogens by using protein inhibitors of cell wall degrading enzymes.
No full textBroad-spectrum and durable resistance is one of the most attracting perspective in breeding projects aimed at increasing crop resistance. Since most microbial pathogens need to surmount the plant cell wall to penetrate the host tissue, the reinforcement of this complex compartment should increase the capacity of the host plant to resist the attack of different pathogens.
We pursued this goal by enhancing the host ability to abolish or limit the activity of Cell Wall Degrading Enzymes (CWDEs) secreted by the pathogens during the penetration and colonization of the host tissue. We concentrated our efforts on the containment of the activity of two different CWDEs: the PolyGalacturonases (PGs) and the xylanase inhibitors (XI). PolyGalacturonases (PGs) are among the first CWDEs secreted by fungal pathogens during infection and in some pathosystems they are virulence factors. PGs depolymerize the cell wall pectin, a minor components of the wheat cell wall, and are inhibited by Polygalacturonase Inhibiting proteins (PGIPs). PG activity is also negatively affected by an high degree of pectin methyl esterification. The level of pectin methyl esterification is controlled by the activity of pectin methylesterases (PMEs), which remove the methyl groups, and by its protein inhibitor called Pectin MethylEsterase Inhibitor (PMEI). Thus, indirectly PMEI may negatively affect the activity of PGs by maintaining the pectin with a high degree of methyl esterification. Xylanases are key enzymes in the degradation of arabinoxylans, a main component of the wheat cell wall. These enzymes have been shown to be virulence factors for the fungal pathogens Botrytis cinerea and Mycosphaerella graminicola. The activity of microbial xylanases is controlled in vitro by xylanase inhibitors (XIs) localized in the plant cell wall. However, no evidences in planta for a role of XIs in plant resistance against pathogens have not been reported yet. By using a transgenic approach we showed that PGIP or PMEI can endows durum wheat with new capacities to control the activity of fungal PGs, possibly through a direct interaction or indirectly by modifying the level and pattern of methyl esterification of cell wall pectin. Similarly, transgenic durum wheat plants over-expressing TAXI-III, a member of the TAXI-type XIs, showed new abilities to control fungal xylanases in all tissues, including those that normally do not accumulate this inhibitor. By phytopathogenic tests we demonstrated that these modifications are effective in limiting wheat diseases caused by the fungal pathogens Fusarium graminearum and Bipolaris sorokiniana. We showed also that the reduction of disease symptoms is associated with a reduced accumulation of mycotoxins. In conclusion, these results indicated that the host cell wall polysaccharides, irrespective of their amount and type, plays a key role as functional barrier against different pathogens and that the increased accumulation of glycosidase inhibitors can contribute to maintain their integrity and improve wheat resistance against fungal pathogens
Expression of a wheat xylanase inhibitor and of a Fusarium graminearum xylanase in plants increase resistance to pathogens.
No full textDuring host plant infection, pathogens produce many cell wall degrading enzymes (CWDE) in order to colonize the host tissue and also to obtain nutrients. Xylanases are hydrolytic enzymes with a dual role: they catalyze the hydrolysis of xylan, the largest structural polysaccharide of plant cell wall, and some of them can cause necrosis in the host tissue. Since a wheat xylanase inhibitor (TAXI-I) has been shown to inhibit a Botrytis cinerea xylanase, a well known virulence factor of the fungus, we transiently expressed TAXI-I and TAXI-III inhibitors, which has similar inhibitory capability, in tobacco leaves by agroinfiltration. Total leaves protein extracts expressing TAXIs inhibited fungal xylanase activity and TAXIs agroinfiltrated tobacco plants were less susceptible towards B. cinerea by about 20-25%.
Recently we have identified a Fusarium graminearum xylanase (FGSG_03624) shown to cause H2O2 accumulation in wheat tissues and induction of defense genes in Arabidopsis thaliana; we therefore tested its ability to increase resistance against bacterial and fungal pathogens. Exogenous treatment with the xylanase showed a slight reduction of symptoms caused by Pseudomonas syringae pv. maculicola, while the treatment was ineffective against B. cinerea. To further verify this result we also transiently expressed the xylanase in tobacco plants through agroinfiltration; preliminary infection experiments seem to confirm previous results.
Finally we also produced by floral dip transformation Arabidopsis transgenic plants constitutively expressing TAXI-I, TAXI-III and the xylanase FGSG_03624. Infection experiments of these plants with B. cinerea and P. syringae pv. maculicola are in progress
The xylanase inhibitor TAXI-III is involved in wheat resistance against Fusarium graminearum.
No full textCereals contain xylanase inhibitor proteins (XIs) which inhibit microbial xylanases from glycoside hydrolase families 10 and 11. In wheat, three types of XIs have been identified: Triticum aestivum XI (TAXI), xylanase inhibitor protein (XIP) and thaumatin-like XI (TLXI). Each type of XIs is represented by a multiple number of genes. These inhibitors are considered part of the defence mechanisms that plants use to counteract microbial pathogens. Indeed, XIs are induced by pathogen infection and are responsive to mechanical wounding and jasmonic acid and salicylic acid treatments. They are localized in the apoplastic region and are effective against xylanases of microbial origin and not against endogenous plant xylanases. An additional aspect that reinforces the possibility that the XIs are involved in plant defence derives from the observation that xylaneses are important components during pathogenesis for the fungal pathogens Botrytis cinerea and Septoria tritici. Nevertheless, more direct evidences have not been reported yet. Therefore, we produced a number of transgenic plants over-expressing TAXI-III, a member of the TAXI type XIs that is expressed only in developing caryopsis and roots and is induced by pathogen infection, wounding and elicitor treatments. In order to facilitate the understanding of its possible contribution in wheat defence, we designated the transgenic plants to express Taxi-III constitutively. Results showed that TAXI-III accumulated accumulates in all tissues including those that normally do not accumulate it and its presence endows the transgenic wheat with new inhibition capacity. We show also that TAXI-III is correctly secreted into the apoplast and possesses the expected inhibition capacity against microbial xylanases. In particular, total protein wheat extract or purified TAXI-III from transgenic plants inhibits a purified xylanase from Fusarium graminearum and to some extent the total xylanase activity produced in vitro by the fungal pathogens F. graminearum and Bipolaris sorokiniana. The new inhibition properties of the transgenic tissues correlate with a significant reduction of fusarium Fusarium head Head blight Blight (FHB) disease symptom caused by F. graminearum but do not influence significantly leaf spot symptoms caused by B. sorokiniana. Possible differences on the efficacy of TAXI-III to inhibit specific xylanases produced by the two fungal pathogens during host colonization or the presence of additional factors conditioning host colonization at floral or leaf tissues can be responsible for this different outcome.
In conclusion, our results provide for the first time a straight evidence in planta that XIs are involved in plant defence against fungal pathogens and show the possibility to manipulate TAXI-III accumulation to improve wheat resistance against F. graminearum
Breast cancer follow-up: a national survey of current clinical practice by the centers of Italian Oncological Group of Clinical Research (GOIRC).
No full textBackground: The number of breast cancer (BC) survivors is increasing due to the aging of the population and the improvement of survival rates. Survivors have health care needs including detection of early recurrences, treatment of therapy-related complications and psychological support. No randomized data exist to support any individual follow-up (FU) sequence or protocol. Pphysicians’ adherence to international guidelines is unknown. The aim of this study is to investigate the survivorship care plan in Cancer Centers affiliated to Italian Oncological Group of Clinical Research (GOIRC).
Methods: A questionnaire survey with 12 questions was e-mailed to the members of GOIRC in March 2019. Respondents were asked how they follow-up BC survivors. We have collected the survey data and compared them to national/international guidelines.
Results: 20 out of 30 GOIRC centers completed the survey. The majority of the oncologists (75%) reported to follow AIOM guideline in FU management. Although, 14 respondents (70%) are used to perform routinely tumor markers and imaging tests (chest X-ray and liver ultrasound) as screening tools for early detection of recurrence. Advanced imaging studies (bone scan, CT scan, PET/FDG CT) are routinely recommended in high-risk patients by 4 interviewed. Considering patients on aromatase inhibitors, all the respondents recommend lipid profile and bone density evaluation every two years. Moreover, nutritional counselling is offered in 7 centers (35%). Frequency of checkup is scheduled according with BC risk of relapse in 11 centers (55%), while visits are conducted six-monthly in the other 9 cases. Duration of FU is variable: 60% of interviewed monitor the patients until the end of the adjuvant endocrine therapy while in the other cases checkup is carried on over 10 years. At the end of oncology FU, all the interviewed recommended yearly mammography, in four cases annual tumor markers check is suggested too.
Conclusion
A majority of respondents in Italian Cancer Centers perform more intensive follow-up compared to guidelines recommendations. FU of BC survivors is still an unmet clinical need. Randomized national trial on survivorship care plan should be considered
Safety and efficacy of T-DM1 in HER2 positive metastatic breast cancer patients: a real word experience.
No full textBackground: T-DM1 is an antibody–drug conjugate that combines the antitumor effects of trastuzumab with a cytotoxic antimicrotubule agent that is only released in HER-positive tumor cells. It has been approved for the treatment of patients with HER2 positive metastatic breast cancer (MBC) pre-treated with trastuzumab + taxanes or progressing while on adjuvant trastuzumab, after the pivotal phase III trial EMILIA. The aim of this study is to audit the real life experience with T-DM1 at the University Hospital of Modena.
Material and methods: All patients treated with T-DM1 in our Institution between May 2014 – February 2016 were retroprospectively collected. All patients registered at the time of analysis were evaluated for safety and efficacy. Treatment toxicities were graded according to CTCAE version 4.0. Efficacy was assessed as per clinical practice.
Results: Twenty-two patients have been treated with T-DM1. The median age was 58 years (range 38-77), 50% of them with ECOG 1-2. With regards to tumor characteristics, 72% were hormonal receptor positive BC and 82% of patients had visceral involvement at the beginning of T-DM1. All patients received previous trastuzumab and taxane, 50% received anthracycline-based therapy too. 27% of patients were pre-treated with at least three prior chemotherapy lines for MBC. Pertuzumab was previously administered to one patient, lapatinib to 8 patients. The median number of T-DM1 cycles was 9 (range 1-30), with 50% of patients receiving 5 or more courses. All patients were assessed for efficacy: 36% obtained PR and 18% SD as the best response. The clinical benefit rate (CR+PR+SD>6months) was 45%. The median PFS was 9.0 months (CI 2.8–20.8). Six patients (27%) out of 22 died. Mild grade transaminitis was the most common side effect observed in 50% of patients, followed by fatigue in 41% of patients, thrombocytopenia in 35% and diarrhea in 28%. No grade 3 adverse events were observed, although two hypersensitivity reactions were reported.
Conclusions: T-DM1 administered outside the context of a clinical trial is safe, well tolerated, and with reproducible efficacy, consistent with those published in the EMILIA and TH3RESA studies
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