Fluorescent imaging probes for in vivo ovarian cancer targeted detection and surgery.

Ovarian cancer is the most lethal gynecological cancer, with a survival rate of approximately 40% at five years from the diagno. The first-line treatment consists of cytoreductive surgery combined with chemotherapy (platinum- and taxane-based drugs). To date, the main prognostic factor is related to the complete surgical resection of tumor lesions, including occult micrometastases. The presence of minimal residual diseases not detected by visual inspection and palpation during surgery significantly increases the risk of disease relapse. Intraoperative fluorescence imaging systems have the potential to improve surgical outcomes. Fluorescent tracers administered to the patient may support surgeons for better real-time visualization of tumor lesions during cytoreductive procedures. In the last decade, consistent with the discovery of an increasing number of ovarian cancer-specific targets, a wide range of fluorescent agents were identified to be employed for intraoperatively detecting ovarian cancer. Here, we present a collection of fluorescent probes designed and developed for fluorescence-guided ovarian cancer surgery. Original articles published between 2011 and November 2022 focusing on fluorescent probes, currently under preclinical and clinical investigation, were searched in PubMed. The keywords used were targeted detection, ovarian cancer, fluorescent probe, near-infrared fluorescence, fluorescence-guided surgery, and intraoperative imaging. All identified papers were English-language full-text papers, and probes were classified based on the location of the biological target: intracellular, membrane, and extracellular.

A further pocket or conformational plasticity by mapping COX-1 catalytic site through modified-mofezolac structure-inhibitory activity relationships and their antiplatelet behavior.

Cyclooxygenase enzymes have distinct roles in cardiovascular, neurological, and neurodegenerative disease. They are differently expressed in different type of cancers. Specific and selective COXs inhibitors are needed to be used alone or in combo-therapies. Fully understand the differences at the catalytic site of the two cyclooxygenase (COX) isoforms is still opened to investigation. Thus, two series of novel compounds were designed and synthesized in fair to good yields using the highly selective COX-1 inhibitor mofezolac as the lead compound to explore a COX-1 zone formed by the polar residues Q192, S353, H90 and Y355, as well as hydrophobic amino acids I523, F518 and L352. According to the structure of the COX-1:mofezolac complex, hydrophobic amino acids appear to have free volume eventually accessible to the more sterically hindering groups than the methoxy linked to the phenyl groups of mofezolac, in particular the methoxyphenyl at C4-mofezolac isoxazole. Mofezolac bears two methoxyphenyl groups linked to C3 and C4 of the isoxazole core ring. Thus, in the novel compounds, one or both methoxy groups were replaced by the higher homologous ethoxy, normal and isopropyl, normal and tertiary butyl, and phenyl and benzyl. Furthermore, a major difference between the two sets of compounds is the presence of either a methyl or acetic moiety at the C5 of the isoxazole. Among the C5-methyl series, 12 (direct precursor of mofezolac) (COX-1 IC50 = 0.076 µM and COX-2 IC50 = 0.35 µM) and 15a (ethoxy replacing the two methoxy groups in 12; COX-1 IC50 = 0.23 µM and COX-2 IC50 > 50 µM) were still active and with a Selectivity Index (SI = COX-2 IC50/COX-1 IC50) = 5 and 217, respectively. The other symmetrically substituted alkoxyphenyl moietis were inactive at 50 µM final concentration. Among the asymmetrically substituted, only the 16a (methoxyphenyl on C3-isoxazole and ethoxyphenyl on C4-isoxazole) and 16b (methoxyphenyl on C3-isoxazole and n-propoxyphenyl on C4-isoxazole) were active with SI = 1087 and 38, respectively. Among the set of compounds with the acetic moiety, structurally more similar to mofezolac (SI = 6329), SI ranged between 1.4 and 943. It is noteworthy that 17b (n-propoxyphenyl on both C3- and C4-isoxazole) were found to be a COX-2 slightly selective inhibitor with SI = 0.072 (COX-1 IC50 > 50 µM and COX-2 IC50 = 3.6 µM). Platelet aggregation induced by arachidonic acid (AA) can be in vitro suppressed by the synthesized compounds, without affecting of the secondary hemostasia, confirming the biological effect provided by the selective inhibition of COX-1. A positive profile of hemocompatibility in relation to erythrocyte and platelet toxicity was observed. Additionally, these compounds exhibited a positive profile of hemocompatibility and reduced cytotoxicity. Quantitative structure activity relationship (QSAR) models and molecular modelling (Ligand and Structure based virtual screening procedures) provide key information on the physicochemical and pharmacokinetic properties of the COX-1 inhibitors as well as new insights into the mechanisms of inhibition that will be used to guide the development of more effective and selective compounds. X-ray analysis was used to confirm the chemical structure of 14 (MSA17).

Harmaline to Human Mitochondrial Caseinolytic Serine Protease Activation for Pediatric Diffuse Intrinsic Pontine Glioma Treatment.

Diffuse intrinsic pontine glioma (DIPG), affecting children aged 4-7 years, is a rare, aggressive tumor that originates in the pons and then spreads to nearby tissue. DIPG is the leading cause of death for pediatric brain tumors due to its infiltrative nature and inoperability. Radiotherapy has only a palliative effect on stabilizing symptoms. In silico and preclinical studies identified ONC201 as a cytotoxic agent against some human cancer cell lines, including DIPG ones. A single-crystal X-ray analysis of the complex of the human mitochondrial caseinolytic serine protease type C (hClpP) and ONC201 (PDB ID: 6DL7) allowed hClpP to be identified as its main target. The hyperactivation of hClpP causes damage to mitochondrial oxidative phosphorylation and cell death. In some DIPG patients receiving ONC201, an acquired resistance was observed. In this context, a wide program was initiated to discover original scaffolds for new hClpP activators to treat ONC201-non-responding patients. Harmaline, a small molecule belonging to the chemical class of ß-carboline, was identified through Fingerprints for Ligands and Proteins (FLAP), a structure-based virtual screening approach. Molecular dynamics simulations and a deep in vitro investigation showed interesting information on the interaction and activation of hClpP by harmaline.

Experiential techniques and therapeutic relationship in the treatment of narcissistic personality disorder: The case of Laura.

Experiential techniques can be used to address maladaptive interpersonal patterns in patients with personality disorders (PDs) as long as they are delivered minding about the therapeutic relationship. We present the case study of Laura, a 38-year-old woman presenting with covert narcissism, generalized anxiety disorder, depression, and complicated grief treated with metacognitive interpersonal therapy. Laura initially refused to engage in any experiential work out of fear of being judged and abandoned by her therapist. To navigate this therapeutic obstacle, the therapist focused on exploring and eventually repairing early alliance ruptures. Thereafter, Laura engaged in experiential work, which helped her address her narcissistic interpersonal patterns. After 2 years, Laura's symptoms and narcissistic problematic behaviors decreased. This case study can help us understand how experiential techniques can be successfully used in PD psychotherapy as long as attention to the therapy relationship is paid.

Fluorochrome Selection for Imaging Intraoperative Ovarian Cancer Probes.

The identification and removal of all gross and microscopic tumor to render the patient disease free represents a huge challenge in ovarian cancer treatment. The presence of residual disease is an independent negative prognostic factor. Herein, we describe the synthesis and the "in vitro" evaluation of compounds as cyclooxygenase (COX)-1 inhibitors, the COX-1 isoform being an ovarian cancer biomarker, each bearing fluorochromes with different fluorescence features. Two of these compounds N-[4-(9-dimethylimino-9H-benzo[a]phenoxazin-5-ylamino) butyl]-2-(3,4-bis(4-methoxyphenyl)isoxazol-5-yl)acetamide chloride (RR11) and 3-(6-(4-(2-(3,4-bis(4-methoxyphenyl)isoxazole-5-yl)acetamido)butyl)amino-6-oxohexyl)-2-[7-(1,3-dihydro-1,1-dimethyl-3-ethyl 2H-benz[e]indolin-2-yl-idene)-1,3,5-heptatrienyl]-1,1-dimethyl-3-(6-carboxilato-hexyl)-1H-benz[e]indolium chloride, 23 (MSA14) were found to be potent and selective inhibitors of cyclooxygenase (COX)-1 "in vitro", and thus were further investigated "in vivo". The IC50 values were 0.032 and 0.087 µM for RR11 and 23 (MSA 14), respectively, whereas the COX-2 IC50 for RR11 is 2.4 µM while 23 (MSA14) did not inhibit COX-2 even at a 50 µM concentration. Together, this represented selectivity index = 75 and 874, respectively. Structure-based virtual screening (SBVS) performed with the Fingerprints for Ligands and Proteins (FLAP) software allowed both to differentiate highly active compounds from less active and inactive structures and to define their interactions inside the substrate-binding cavity of hCOX1. Fluorescent probes RR11 and 23 (MSA14), were used for preliminary near-infrared (NIR) fluorescent imaging (FLI) in human ovarian cancer (OVCAR-3 and SKOV-3) xenograft models. Surprisingly, a tumor-specific signal was observed for both tested fluorescent probes, even though this signal is not linked to the presence of COX-1.

Face-to-face versus distance learning in a seaside area: the teacher's point of view.

The total or partial replacement of face-to-face teaching with distance teaching brings a number of problems for teachers, children and families. Recently, in our province in Southern Italy, in a seaside area, we conducted a survey to assess the experiences of high school teachers faced with distance learning during the COVID-19 pandemic, with the purpose of examining the real impact of these dramatic changes, both from social and health perspectives. From the preliminary aspects of this survey it emerges that it is difficult to univocally consider the effectiveness of distance learning in such a complex territory, especially in a seaside area. This experience will serve us to reflect in the future on a school tailored to the individual student by a permanent integration of face-to-face forms with distance learning.

Building the alliance and using experiential techniques in the early phases of psychotherapy for avoidant personality disorder.

Individuals experiencing avoidant personality disorder (AvPD) tend to make sense of social interactions via maladaptive self-and other attributions. They also experience difficulties in recognizing emotions. A further feature of AvPD psychopathology is the tendency to resort to maladaptive coping strategies, such as behavioral avoidance and perfectionism. Despite its impact, psychological treatments for AvPD remains poorly investigated. Herein, we describe the first five sessions of Metacognitive Interpersonal Therapy with a 28-year-old woman, whose treatment goal was to reduce social avoidance. We describe how this goal was achieved through a combination of working through the therapeutic relationship, alongside experiential techniques such as guided imagery, rescripting, and bodily work. Through this treatment configuration, the patient was able to increase self-awareness of her own emotions, enabling her to realize that she was guided by rigid schemas; specifically seeing herself as inadequate and others as judgmental. Finally, implications for the treatment of AvPD are discussed.

Impact of novel coronavirus Disease-19 (COVID-19) pandemic in Italian pediatric emergency departments: a national survey.

BACKGROUND: Coronavirus Disease-19 (COVID-19) has rapidly become a pandemic emergency, distressing health systems in each affected country. Preparation strategies for managing this pandemic have been keys to face the COVID-19 surge all over the world and all levels of care. MATERIALS AND METHODS: During the epidemic, the Italian society of pediatric emergency-urgency (SIMEUP) promoted a national survey aiming to evaluate preparedness and response of pediatric emergency departments (PED) critical in ensuring optimal management of COVID-19 cases. RESULTS: Our results suggest that Italian PED have promptly set a proactive approach to the present emergency. 98.9% of the hospitals have defined special pathways and assistive protocols concerning the management of pediatric COVID-19 cases. The highest percentage of application of the measures for preventive and protective for COVID-19 concerned the use of personal protective equipments. CONCLUSIONS: Results show that the following measures for pediatric patients, admitted in PED, have been promptly implemented throughout the whole country: eg. use of protective devices, pre-triage of patients accessing the hospital. Despite COVID-19 being a new threat, we have shown that by developing an easy-to-follow decision algorithm and clear plans for the interventional platform teams, we can ensure optimal health care workers and patients' safety.

El Cambio De Los Patrones Corporales Relacionales En La Terapia Metacognitiva Interpersonal / Changing Embodied Relational Patterns In Metacognitive Interpersonal Therapy

Las personas con trastornos de personalidad tienden a atribuir significados según patrones mentales estereotipados que les dificultan alcanzar una adaptación y satisfacción social. Estos patrones van más allá de ser meras representaciones cognitivas sobre uno mismo y los demás, sino que están repletos de emociones, disposiciones de conducta y experiencias somáticas. El objetivo principal de este trabajo es presentar cómo la terapia metacognitiva interpersonal trabaja con los patrones corporales a través del uso de imágenes mentales y ejercicios sensoriomotores. Como se expone, este tipo de técnicas ayudan a revisar los componentes corporales de los patrones interpersonales desadaptativos y promueven la aparición de otros nuevos más saludables. Se pretende que los patrones resultantes incluyan aspectos más funcionales que impidan la puesta en marcha de las estrategias de afrontamiento impulsadas por los esquemas problemáticos. A través de la exposición de un caso clínico, se subraya que el trabajo experiencial debe llevarse siempre a cabo en el contexto de una regulación constante de la relación terapéutica que permita detectar cualquier posible impasse o ruptura. Igualmente, se muestra cómo el uso de ciertas técnicas en las fases iniciales puede permitir una formulación más dinámica y enriquecida de los esquemas disfuncionales. Finalmente, se discuten algunas implicaciones clínicas y se sugiere el trabajo experiencial como un componente crucial en el tratamiento de pacientes con problemas interpersonales graves, como ocurre en los trastornos de personalidad. (AU)

Individuals with personality disorders tend to attribute meaning according to stereotyped relationship patterns which prevent them from achieving social adaptation and fulfilment. These mental patterns are more than mere cognitive representations of the self and others. They are embodied and laden with affect, behavioral dispositions, and somatic experiences. The main purpose of this workis to present how metacognitive interpersonal therapy provides a platform for changing embodied patterns, via imagery and sensorimotor work. As discussed, these techniques facilitate the revision of the embodied component of maladaptive patterns and promote the emergence of new and healthier patterns. These new patterns comprise more adaptive aspects and corresponding lyimpede the enactment of previous maladaptive coping strategies that were driven by pathological schemas. We note howexperiential work is best performed in a context of constant regulation of the therapeutic relationship, in order to detect any possiblerelational impasses and ruptures, reflecting on them until they are repaired. We also show the use of techniques in the initial phaseof therapy to allow a more dynamic and rich case formulation. Finally, we discuss the implications of how experiential work mightbe a crucial component in psychotherapy for persons experiencing severe interpersonal problems such as personality disorders. (AU)

Diffuse Intrinsic Pontine Glioma (DIPG): Breakthrough and Clinical Perspective.

Diffuse intrinsic pontine glioma (DIPG) mainly affects children with a median age of 6-7 years old. It accounts for 10% of all pediatric tumors. Unfortunately, DIPG has a poor prognosis, and the median survival is generally less than 16-24 months independently from the treatment received. Up to now, children with DIPG are treated with focal radiotherapy alone or in combination with antitumor agents. In the last decade, ONC201 known as dopamine receptor antagonist was uncovered, by a high throughput screening of public libraries of compounds, to be endowed with cytotoxic activity against several cancer cell lines. Efforts were made to identify the real ONC201 target, responsible for its antiproliferative effect. The hypothesized targets were the Tumor necrosis factor-Related Apoptosis-Inducing Ligand stimulation (TRAIL), two oncogenic kinases (ERK/AKT system) that target the same tumor-suppressor gene (FOXO3a), dopamine receptors (DRD2 and DRD3 subtypes) and finally the mitochondrial Caseynolitic Protease P (ClpP). ONC201 structure-activity relationship is extensively discussed in this review, together with other two classes of compounds, namely ADEPs and D9, already known for their antibiotic activity but noteworthy to be discussed and studied as potential "leads" for the development of new drugs to be used in the treatment of DIPG. In this review, a detailed and critical description of ONC201, ADEPs, and D9 pro-apoptotic activity is made, with particular attention to the specific interactions established with its targets that also are intimately described. Pubmed published patents and clinical trial reports of the last ten years were used as the bibliographic source.

Cyclooxygenase Inhibition Safety and Efficacy in Inflammation-Based Psychiatric Disorders.

According to the World Health Organization, the major psychiatric and neurodevelopmental disorders include major depression, bipolar disorder, schizophrenia, and autism spectrum disorder. The potential role of inflammation in the onset and progression of these disorders is increasingly being studied. The use of non-steroidal anti-inflammatory drugs (NSAIDs), well-known cyclooxygenase (COX) inhibitors, combined with first-choice specific drugs have been long investigated. The adjunctive administration of COX inhibitors to classic clinical treatments seems to improve the prognosis of people who suffer from psychiatric disorders. In this review, a broad overview of the use of COX inhibitors in the treatment of inflammation-based psychiatric disorders is provided. For this purpose, a critical analysis of the use of COX inhibitors in the last ten years of clinical trials of the major psychiatric disorders was carried out.

Twenty-Five Year Experience with Laparoscopic Cholecystectomy in the Pediatric Population-From 10 mm Clips to Indocyanine Green Fluorescence Technology: Long-Term Results and Technical Considerations.

Background: This study aimed to review our 25-year experience with pediatric laparoscopic cholecystectomy (LC) to assess its long-term outcome. Materials and Methods: The records of 215 children (127 girls and 88 boys) who underwent LC for the past 25 years (1993-2018) were retrospectively reviewed. All patients had a symptomatic cholelithiasis. The cholelithiasis was idiopathic in 185 patients (86%) and secondary in 30 patients (14%). A four-trocar technique was always adopted and cystic duct and cystic artery were clipped using 10-mm clips in the first 35 cases (16.3%) and 5-mm clips in the following 180 patients (83.7%). In the last 15 cases, indocyanine green (ICG)-enhanced fluorescence was adopted intraoperatively for a better identification of the anatomy of gallbladder and biliary tree. Results: The average operative time was 69 minutes and fell down to 52 minutes after introduction of ICG fluorescence (P = .001). Fifteen anatomic anomalies (6.9%), involving bile duct in 5 cases and cystic artery in 10 cases, were recorded. Technical problems were reported intraoperatively in 6 cases (2.8%). We recorded 4 postoperative Clavien IIIb complications (1.9%): 1 bleeding from the cystic artery, 1 dislocation of the clips on the cystic duct, and 2 iatrogenic injuries to the main bile duct managed with choledojejunostomy in 1 case and suture of the choleducus over a stent in the second case. We also recorded 3 umbilical granulomas (1.4%) (Clavien II). Conclusions: LC is a standardized and effective procedure to perform in children. Our 25-year experience showed that major complications (Clavien IIIb) can occur even in experienced surgeons' hands. Age, weight, and preoperative cholecystitis were significantly associated with the risk of bile duct injury in our series. Considering its versatility and safety, we believe that ICG fluorescence technology may be adopted in every LC to ease the dissection and reduce the likelihood of complications.