MITO END-3: Efficacy of Avelumab immunotherapy according to molecular profiling in first-line endometrial cancer therapy.

BACKGROUND: Immunotherapy combined with chemotherapy significantly improves progression-free survival compared to first-line chemotherapy alone in advanced endometrial cancer, with a much larger effect size in microsatellite-instability high (MSI-H) cases. New biomarkers might help to select patients that may have benefit among those with a microsatellite-stable (MSS) tumor. METHODS: In a pre-planned translational analysis of the MITO END-3 trial, we assessed the significance of genomic abnormalities in patients randomized to standard carboplatin/paclitaxel without or with avelumab. RESULTS: Out of 125 randomized patients, 109 had samples eligible for next-generation sequencing (NGS) analysis, and 102 had MSI tested. According to The Cancer Genome Atlas (TCGA), there were 29 cases MSI-H, 26 MSS TP53 wild-type (wt), 47 MSS TP53 mutated (mut), and one case with POLE mutation. Four mutated genes were present in more than 30% of cases: TP53, PIK3CA, ARID1A, and PTEN. Eleven patients (10%) had a BRCA1/2 mutation (five in MSI-H and six in MSS). High TMB (≥10 Muts/Mb) was observed in all MSI-H patients, in four out of 47 MSS/TP53 mut, and no case in the MSS/TP53 wt category. The effect of avelumab on progression-free survival significantly varied according to TCGA categories, being favorable in MSI-H and worst in MSS/TP53 mut (P interaction=0.003); a similar non-significant trend was seen in survival analysis. ARID1A and PTEN also showed a statistically significant interaction with treatment effect, which was better in the presence of the mutation (ARID1A P interaction=0.01; PTEN P interaction=0.002). CONCLUSION: The MITO END-3 trial results suggest that TP53 mutation is associated with a poor effect of avelumab, while mutations of PTEN and ARID1A are related to a positive effect of the drug in patients with advanced endometrial cancer.

Occult invasive cervical cancer, FIGO stage III, with a negative Pap smear test - clinical presentation and brief review of the literature.

Occult cervical cancer is rare and is diagnosed incidentally after a simple hysterectomy. The staging upon histological examination is usually International Federation of Gynecology and Obstetrics (FIGO) stage I, rarely higher with negative preoperative diagnostic tests such as a Pap smear. The clinical case in question is a rare case of cervical carcinoma diagnosed at the time of hysterectomy with a negative exo-endocervical Pap smear, diagnostic tests including transvaginal ultrasound, abdominal magnetic resonance imaging and abdominal computed tomography with a diagnosis of degenerating myoma or suspected sarcoma. In the operating theatre, the surgical radicality was modified and the operation was completed with removal of the parameters, vaginal collar and bilateral pelvic lymphadenectomy. The final histological examination indicated FIGO stage III, for which the patient underwent radiotherapy and chemotherapy.

Bat diversity boosts ecosystem services: Evidence from pine processionary moth predation.

Coniferous forests contribute to the European economy; however, they have experienced a decline since the late 1990s due to an invasive pest known as the pine processionary moth, Thaumetopoea pityocampa. The impacts of this pest are increasingly exacerbated by climate change. Traditional control strategies involving pesticides have had negative effects on public health and the environment. Instead, forest managers seek a more ecological and sustainable approach to management that promotes the natural actions of pest control agents. This study aims to evaluate the role of bats in suppressing pine processionary moths in pine forests and examine how the bat community composition and abundance influence pest consumption. Bats were sampled in the mountainous environment of the Serra da Estrela in central Portugal to collect faecal samples for DNA meta-barcoding analysis. We assessed the relationship between a) bat richness, b) bat relative abundance, c) bat diet richness, and the frequency of pine processionary moth consumption. Our findings indicate that sites with the highest bat species richness and abundance exhibit the highest levels of pine processionary moth consumption. The intensity of pine processionary moth consumption is independent of insect diversity within the site. The highest occurrence of pine processionary moth presence in bat diets is primarily observed in species that forage in cluttered habitats. A typical predator of pine processionary moths among bats is likely to be a forest-dwelling species that specialises in consuming Lepidoptera. These species primarily use short-range echolocation calls, which are relatively inaudible to tympanate moths, suitable for locating prey in cluttered environments, employing a gleaning hunting strategy. Examples include species from the genera Plecotus, Myotis, and Rhinolophus. This study enhances our understanding of the potential pest consumption services provided by bats in pine forests. The insights gained from this research can inform integrated pest management practices in forestry.

The role of mesotherapy in the management of spinal pain. A randomized controlled study.

Background: Mesotherapy is a technique through which active ingredients are administered into the thickness of the skin in order to increase the local analgesic effect. Methods: 141 patients with spinal pain not responding to systemic therapy with NSAIDs were randomized to receive one or more intra-cutaneous drugs on a weekly basis. Results: All patients achieved a pain reduction of at least 50% compared to baseline, and all tolerated the therapy without having to resort to systemic drug dose increases. Conclusions: The data from our study show that the active ingredients infiltrated into the skin induce a mesodermal modulation between the infiltrated liquid and the cutaneous nervous and cellular structures from which the typical drug-saving effect of mesotherapy arises. Although further studies are needed to establish how to integrate mesotherapy in various clinical settings, it appears to be a useful technique available to the practicing physician. This research is also useful in guiding future clinical research.

The role of miR-139-5p in radioiodine-resistant thyroid cancer.

PURPOSE: Radioiodine I-131 (RAI) is the therapy of choice for differentiated thyroid cancer (DTC). Between 5% and 15% of DTC patients become RAI refractory, due to the loss of expression/function of iodide metabolism components, especially the Na/I symporter (NIS). We searched for a miRNA profile associated with RAI-refractory DTC to identify novel biomarkers that could be potential targets for redifferentiation therapy. METHODS: We analyzed the expression of 754 miRNAs in 26 DTC tissues: 12 responsive (R) and 14 non-responsive (NR) to RAI therapy. We identified 15 dysregulated miRNAs: 14 were upregulated, while only one (miR-139-5p) was downregulated in NR vs. R tumors. We investigated the role of miR-139-5p in iodine uptake metabolism. We overexpressed miR-139-5p in two primary and five immortalized thyroid cancer cell lines, and we analyzed the transcript and protein levels of NIS and its activation through iodine uptake assay and subcellular protein localization. RESULTS: The finding of higher intracellular iodine levels and increased cell membrane protein localization in miR-139-5p overexpressing cells supports the role of this miRNA in the regulation of NIS function. CONCLUSIONS: Our study provides evidence of miR-139-5p involvement in iodine uptake metabolism and suggests its possible role as a therapeutic target in restoring iodine uptake in RAI-refractory DTC.

Alternative academic approaches for testing homologous recombination deficiency in ovarian cancer in the MITO16A/MaNGO-OV2 trial.

BACKGROUND: The detection of homologous recombination deficiency (HRD) can identify patients who are more responsive to platinum and poly ADP ribose polymerase inhibitors (PARPi). MyChoice CDx (Myriad) is the most used HRD test in ovarian cancer (OC). However, some limitations of commercial tests exist, because of the high rate of inconclusive results, costs, and the impossibility of evaluating functional resistance mechanisms. PATIENTS AND METHODS: Two academic genomic tests and a functional assay, the RAD51 foci, were evaluated to detect HRD. One hundred patients with high-grade OC enrolled in the MITO16A/MaNGO-OV2 trial and treated with first-line therapy with carboplatin, paclitaxel, and bevacizumab were analyzed. RESULTS: The failure rate of the two genomic assays was 2%. The sensitivity in detecting HRD when compared with Myriad was 98.1% and 90.6%, respectively. The agreement rate with Myriad was 0.92 and 0.87, with a Cohen's κ coefficient corresponding to 0.84 and 0.74, respectively. For the RAD51 foci assay, the failure rate was 30%. When the test was successful, discordant results for deficient and proficient tumors were observed, and additional HRD patients were identified compared to Myriad; sensitivity was 82.9%, agreement rate was 0.65, and Cohen's κ coefficient was 0.18. The HRD detected by genomic assays and residual tumor at primary surgery and stage was correlated with progression-free survival at multivariate analysis. CONCLUSIONS: Results suggest the feasibility of academic tests for assessing HRD status that show robust concordance with Myriad and correlation with clinical outcome. The contribution of the functional information related to the RAD51 foci test to the genomic data needs further investigation.

Role of the Mosaic Cisternal Maturation Machinery in Glycan Synthesis and Oncogenesis.

Tumorigenesis is associated with the deregulation of multiple processes, among which the glycosylation of lipids and proteins is one of the most extensively affected. However, in most cases, it remains unclear whether aberrant glycosylation is a cause, a link in the pathogenetic chain, or a mere consequence of tumorigenesis. In other cases, instead, studies have shown that aberrant glycans can promote oncogenesis. To comprehend how aberrant glycans are generated it is necessary to clarify the underlying mechanisms of glycan synthesis at the Golgi apparatus, which are still poorly understood. Important factors that determine the glycosylation potential of the Golgi apparatus are the levels and intra-Golgi localization of the glycosylation enzymes. These factors are regulated by the process of cisternal maturation which transports the cargoes through the Golgi apparatus while retaining the glycosylation enzymes in the organelle. This mechanism has till now been considered a single, house-keeping and constitutive function. Instead, we here propose that it is a mosaic of pathways, each controlling specific set of functionally related glycosylation enzymes. This changes the conception of cisternal maturation from a constitutive to a highly regulated function. In this new light, we discuss potential new groups oncogenes among the cisternal maturation machinery that can contribute to aberrant glycosylation observed in cancer cells. Further, we also discuss the prospects of novel anticancer treatments targeting the intra-Golgi trafficking process, particularly the cisternal maturation mechanism, to control/inhibit the production of pro-tumorigenic glycans.

Intradermal therapy (mesotherapy): the lower the better.

BACKGROUND: Intradermal therapy (mesotherapy) is a technique used to inject drugs into the surface layer of the skin. The intradermal micro deposit allows to modulate the kinetics of drugs, slowing down its absorption and prolonging the local mechanism of action. This technique is applied in the treatment of some forms of localized pain when a systemic drug-saving effect is useful, when it is necessary to synergize with other pharmacological or non-pharmacological thera-pies, when other therapies have failed or cannot be used. AIM: The purpose of our study was to evaluate the effect of a mixture with respect to its lower concentration. We also wanted to evaluate the number of sessions needed to reach the therapeutic goal (50% reduction in pain from baseline) in patients with acute or chronic neck pain. METHOD: We analyzed retrospectively data from 62 patients with cervicobrachial pain treated with intradermal drugs. Group A received a mixture of drugs; group B received half the dose of drugs. RESULTS: Patients who received a lower concentration of drugs achieved similar results to those who received a higher dose. The therapeutic goal was achieved on average with 3.5 + 1.7 sessions on a weekly basis (min 1; max 9). Subjects in group A required 4+1.7 treatments (min 1; max 9), while subjects in group B required 3+1.5 treatments (min 1; max 7). CONCLUSIONS: Our study confirms that even a lower dose of drugs can induce a clinically useful result. This study confirms that the useful effect of mesotherapy is only partly due to the pharmacological action. Further randomized prospective studies are needed to standardize the technique in the various pain syndromes, but it is recommended to follow the guidelines of the Italian Society of Mesotherapy to ensure patients receive appropriate treatment.

A choroid plexus metastasis of a prostatic adenocarcinoma mimicking a choroid plexus carcinoma: A case report.

A multicystic intraventricular tumour of the right ventricular atrium was incidentally diagnosed on follow-up imaging of a 61-year-old man with a history of prostatic adenocarcinoma. Surgical resection of the lesion was performed after a one-year radio-clinical follow-up due to progressive expansion of the lesion size and a rising prostate specific antigen blood-level. Morphological features with papillary pattern on pathological examination were compatible with malignant adenocarcinoma or choroid plexus carcinoma. The immunoprofile was conclusive for an exceptional choroid plexus metastasis (CPM) of a prostatic adenocarcinoma. To our knowledge, this is the first report of a proven prostatic origin of a CPM.

Two Synchronous Neonatal Tumors: An Extremely Rare Case.

We report a case of a newborn with two synchronous tumors-sialoblastoma and hepatoblastoma-diagnosed at 20 weeks of gestation by magnetic resonance imaging (MRI) and ultrasonography (US). The aim of this study was to describe the management of this case together with a review of the literature. Our patient had a large facial tumor associated with extremely high alpha-fetoprotein levels. Diagnosis of the tumors was made by surgical biopsy, showing typical features in both. Sialoblastoma is a potentially aggressive tumor. In our case, the Ki67 index in the sialoblastoma was between 20 and 30%, indicating a possibly unfavorable behavior. The infant underwent surgery and chemotherapy in different steps. Complete surgical resection with clean margins is considered to be the best treatment option for sialoblastoma. Only four similar cases were previously reported. Timely management by a multidisciplinary team is essential in these difficult cases. In our patient, outcome was good at the time of this report.

Stereotactic ablative radiotherapy in castration-resistant prostate cancer patients with oligoprogression during androgen receptor-targeted therapy.

OBJECTIVES: To report outcomes of stereotactic body radiotherapy (SBRT) in metastatic castration-resistant prostate cancer (mCRPC) patients with oligoprogression (≤ 5 metastases) during first-line treatment with androgen receptor-targeted therapy (ARTT). PATIENTS AND METHODS: Retrospective multi-institutional analysis of mCRPC patients treated with SBRT to oligoprogressive lesions during ARTT. End-points were time to next-line systemic treatment (NEST), radiological progression-free survival (r-PFS) and overall survival (OS). Toxicity was registered according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Survival analysis was performed using the Kaplan-Meier method, univariate and multivariate analysis (MVA) were performed. RESULTS: Data from 34 patients were analyzed. Median NEST-free survival, r-PFS, and OS were 16.97, 13.47, and 38.3 months, respectively. At MVA, factors associated with worse NEST-free survival and r-PFS were polymetastatic burden at diagnosis of metastatic hormone-sensitive disease (hazard ratio [HR] 3.66, p = 0.009; HR 3.03, p = 0.034), PSA ≤ 7 ng/ml at mCRPC diagnosis (HR 0.23, p = 0.017; HR 0.19, p = 0.006) and PSADT ≤ 3 months at mCRPC diagnosis (HR 3.39, p = 0.026; HR 2.79, p = 0.037). Polymetastatic state at mHSPC diagnosis was associated with a decreased OS (HR 4.68, p = 0.029). No patient developed acute or late grade ≥ 2 toxicity. CONCLUSION: Our results suggest that SBRT in oligoprogressive mCPRC is safe, effective and seems to prolong the efficacy of the ongoing systemic treatment positively affecting disease progression. Prospective trials are needed.

Evidence based recommendations on mesotherapy: an update from the Italian society of Mesotherapy.

INTRODUCTION: Mesotherapy, also known as local intradermal therapy, widely used all over the world, is a technique used to inject substances into the surface layer of the skin. There are no international guidelines for the correct use of this technique and in many countries, it is still applied empirically without valid patient consent. The Italian society of mesotherapy has planned a study to assess the rationale and clinical applications based on current evidence. METHODS: An independent steering committee, based on the available scientific literature, has formulated a series of clinical questions. 21 experts responded by writing an evidence-based document. From this document 30 statements were obtained which were presented to 114 experts using the Delphi method. RESULTS: 28 statements reached a broad agreement on definition, technique, pharmacological rationale, indications and some crucial ethical aspect. CONCLUSIONS: Although further studies are needed to establish the clinical role of this technique in each field of application, our statements recommend the correct application according to the needs of the individual patient in full respect of ethics.

Water-soluble chlorophyll-binding proteins from Brassica oleracea allow for stable photobiocatalytic oxidation of cellulose by a lytic polysaccharide monooxygenase.

BACKGROUND: Lytic polysaccharide monooxygenases (LPMOs) are indispensable redox enzymes used in industry for the saccharification of plant biomass. LPMO-driven cellulose oxidation can be enhanced considerably through photobiocatalysis using chlorophyll derivatives and light. Water soluble chlorophyll binding proteins (WSCPs) make it is possible to stabilize and solubilize chlorophyll in aqueous solution, allowing for in vitro studies on photostability and ROS production. Here we aim to apply WSCP-Chl a as a photosensitizing complex for photobiocatalysis with the LPMO, TtAA9. RESULTS: We have in this study demonstrated how WSCP reconstituted with chlorophyll a (WSCP-Chl a) can create a stable photosensitizing complex which produces controlled amounts of H2O2 in the presence of ascorbic acid and light. WSCP-Chl a is highly reactive and allows for tightly controlled formation of H2O2 by regulating light intensity. TtAA9 together with WSCP-Chl a shows increased cellulose oxidation under low light conditions, and the WSCP-Chl a complex remains stable after 24 h of light exposure. Additionally, the WSCP-Chl a complex demonstrates stability over a range of temperatures and pH conditions relevant for enzyme activity in industrial settings. CONCLUSION: With WSCP-Chl a as the photosensitizer, the need to replenish Chl is greatly reduced, enhancing the catalytic lifetime of light-driven LPMOs and increasing the efficiency of cellulose depolymerization. WSCP-Chl a allows for stable photobiocatalysis providing a sustainable solution for biomass processing.

Topical toluidine blue-mediated photodynamic therapy for the treatment of oral lichen planus.

Photodynamic Therapy (PDT) is a minimally invasive approach that has shown promising results in management of oral, head and neck lesions. PDT can be used alone or in combination with other conventional treatments (surgery, chemotherapy, radiotherapy). Oral Lichen Planus (OLP) is a mucosal and cutaneous chronic disease characterized by an autoimmune insult of basal keratinocytes. We aim to evaluate the feasibility of topical toluidine blue-mediated PDT for the treatment of oral cavity multifocal homogeneous white lesions by oral lichen planus without dysplastic features.

Biological versus Clinical Risk Factors in Acute Myeloid Leukemia: Is There a Winner?

We present a case of a patient with a three-month history of peripheral blood cytopenia without a confirmed diagnosis of myelodysplastic syndrome, who developed a favourable-risk acute myeloid leukemia (AML), according to the European Leukemia Net (ELN) criteria. The patient achieved a complete remission with incomplete platelet recovery (CRi) after induction. The patient achieved the morphological CR after the first consolidation and completed the first-line treatment with a syngeneic stem cell transplantation (SCT). A disease relapse occurred after one year of CR (blast cell count in the bone marrow 15%), and the patient was offered a haplo-SCT, which he refused due to personal reasons. In this paper, we discuss the interplay between clinical and biological risk factors in non-high-risk AML patients and speculate that some old clinical risk factors (e.g., age of the patient, achievement of CR after induction, and previous history of myelodysplastic syndrome) may still impact on the treatment decision algorithm of some of these patients.

Expression and secretion of a lytic polysaccharide monooxygenase by a fast-growing cyanobacterium.

BACKGROUND: Cyanobacteria have the potential to become next-generation cell factories due to their ability to use CO2, light and inorganic nutrients to produce a range of biomolecules of commercial interest. Synechococcus elongatus UTEX 2973, in particular, is a fast-growing, genetically tractable, cyanobacterium that has garnered attention as a potential biotechnological chassis. To establish this unique strain as a host for heterologous protein production, we aimed to demonstrate expression and secretion of the industrially relevant TfAA10A, a lytic polysaccharide monooxygenase from the Gram-positive bacterium Thermobifida fusca. RESULTS: Two variations of TfAA10A were successfully expressed in S. elongatus UTEX 2973: One containing the native N-terminal, Sec-targeted, signal peptide and a second with a Tat-targeted signal peptide from the Escherichia coli trimethylamine-N-oxide reductase (TorA). Although the TorA signal peptide correctly targeted the protein to the plasma membrane, the majority of the TorA-TfAA10A was found unprocessed in the plasma membrane with a small fraction of the mature protein ultimately translocated to the periplasm. The native Sec signal peptide allowed for efficient secretion of TfAA10A into the medium with virtually no protein being found in the cytosol, plasma membrane or periplasm. TfAA10A was demonstrated to be correctly cleaved and active on the model substrate phosphoric acid swollen cellulose. Additionally, expression and secretion only had a minor impact on cell growth. The secretion yield was estimated at 779 ± 40 µg L-1 based on densitometric analysis. To our knowledge, this is the highest secretion yield ever registered in cyanobacteria. CONCLUSIONS: We have shown for the first time high-titer expression and secretion of an industrially relevant and catalytically active enzyme in S. elongatus UTEX 2973. This proof-of-concept study will be valuable for the development of novel and sustainable applications in the fields of bioremediation and biocatalysis.

Presence of humans and domestic cats affects bat behaviour in an urban nursery of greater horseshoe bats (Rhinolophus ferrumequinum).

Proximity to humans is a primary stressor for wildlife, especially in urban habitats where frequent disturbance may occur. Several bat species often roost in buildings but while the effects of disturbance inside the roost are well documented, little is known about those occurring in the proximity of roosts. We tested the effects of anthropogenic stressors on bats by monitoring reactions to disturbance in a colony of greater horseshoe bats (Rhinolophus ferrumequinum). We assessed disturbance by recording and quantifying the presence of people, domestic cats and noise sources near the roost. Disturbance outside the roost caused the disruption of roosting clusters; when cats entered the roost, bats decreased indoor flight activity. Emergence timing was delayed when people were close to the roost exit, and the delay increased along with the number of people. The occurrence of a cat increased the degree of group clustering during emergence. Cats entered the roost especially when young bats were present, and bat remains occurred in 30% of the cat scats we examined. We show that the occurence of human activities near roosts and free-ranging domestic cats are important albeit overlooked sources of disturbance.

Protein-Polymer Dynamics as Affected by Polymer Coating and Interactions.

We investigate the relaxation dynamics of protein-polymer conjugates by neutron scattering spectroscopy to understand to which extent the coating of a protein by a polymer can replace water in promoting thermal structural fluctuations. For this purpose, we compare the dynamics of protein-polymer mixtures to that of conjugates with a variable number of polymers covalently attached to the protein. Results show that the flexibility of the protein is larger in protein-polymer mixtures than in native protein or in conjugates, even in the dry state. Upon hydration, both the native protein and the conjugate show equivalent dynamics, suggesting that the polymer grafted on the protein surface adsorbs all water molecules.