(+/-)-Gelliusines A and B, two diastereomeric brominated tris-indole alkaloids from a deep water New Caledonian marine sponge (Gellius or Orina sp.)

Two new diastereomeric brominated tris-indole alkaloids occurring as enantiomeric pairs, (±)-gelliusine A (I) and its isomer (±)-gelliusine B, have been isolated from a deep water New Caledonian sponge (Gellius or Orina sp.), whose crude ext. exhibited cytotoxicity against KB cells. Their structures were elucidated by spectroscopic methods including one- and two-dimensional NMR spectroscopy. The major compd., I, which showed very weak cytotoxicity, proved to be active at the serotonin receptor

Lovastatin enhances the replication of the oncolytic adenovirus dl1520 and its antineoplastic activity against anaplastic thyroid carcinoma cells.

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive solid tumors and shows morphological features of a highly malignant, undifferentiated neoplasm. Patients with ATC have a poor prognosis with a mean survival time of 2-6 months; surgery, radiotherapy, and chemotherapy do not improve survival. Gene therapy approaches and oncolytic viruses have been tested for the treatment of ATC. To enhance the antineoplastic effects of the oncolytic adenovirus dl1520 (Onyx-015), we treated ATC cells with lovastatin (3-hydroxy-methylglutaryl-CoA reductase inhibitor), a drug used for the treatment of hypercholesterolemia, which has previously been reported to exert growth-inhibitory and apoptotic activity on ATC cells. Lovastatin treatment significantly increased the effects of dl1520 against ATC cells. The replication of dl1520 in ATC cells was enhanced by lovastatin treatment, and a significant increase of the expression of the early gene E1A 13 S and the late gene Penton was observed in lovastatin-treated cells. Furthermore, lovastatin treatment significantly enhanced the effects of dl1520 against ATC tumor xenografts. Lovastatin treatment could be exploited to increase the efficacy of oncolytic adenoviruses, and further studies are warranted to confirm the feasibility of the approach in ATC patients

Discovery of new molecular entities able to strongly interfere with Hsp90 C-terminal domain

Heat shock protein 90 (Hsp90) is an ATP dependent molecular chaperone deeply involved in the complex network of cellular signaling governing some key functions, such as cell proliferation and survival, invasion and angiogenesis. Over the past years the N-terminal protein domain has been fully investigated as attractive strategy against cancer, but despite the many efforts lavished in the field, none of the N-terminal binders (termed “classical inhibitors”), currently in clinical trials, have yet successfully reached the market, because of the detrimental heat shock response (HSR) that showed to induce; thus, recently, the selective inhibition of Hsp90 C-terminal domain has powerfully emerged as a more promising alternative strategy for anti-cancer therapy, not eliciting this cell rescue cascade. However, the structural complexity of the target protein and, mostly, the lack of a co-crystal structure of C-terminal domain-ligand, essential to drive the identification of new hits, represent the largest hurdles in the development of new selective C-terminal inhibitors. Continuing our investigations on the identification of new anticancer drug candidates, by using an orthogonal screening approach, here we describe two new potent C-terminal inhibitors able to induce cancer cell death and a considerable downregulation of Hsp90 client oncoproteins, without triggering the undesired heat shock response

Interview investigation of insecure attachment styles as mediators between poor childhood care and schizophrenia-spectrum phenomenology

Background Insecure attachment styles have received theoretical attention and some initial empirical support as mediators between childhood adverse experiences and psychotic phenomena; however, further specificity needs investigating. The present interview study aimed to examine (i) whether two forms of poor childhood care, namely parental antipathy and role reversal, were associated with subclinical positive and negative symptoms and schizophrenia-spectrum personality disorder (PD) traits, and (ii) whether such associations were mediated by specific insecure attachment styles. Method A total of 214 nonclinical young adults were interviewed for subclinical symptoms (Comprehensive Assessment of At-Risk Mental States), schizophrenia-spectrum PDs (Structured Clinical Interview for DSM-IV Axis II Disorders), poor childhood care (Childhood Experience of Care and Abuse Interview), and attachment style (Attachment Style Interview). Participants also completed the Beck Depression Inventory-II and all the analyses were conducted partialling out the effects of depressive symptoms. Results Both parental antipathy and role reversal were associated with subclinical positive symptoms and with paranoid and schizotypal PD traits. Role reversal was also associated with subclinical negative symptoms. Angry-dismissive attachment mediated associations between antipathy and subclinical positive symptoms and both angry-dismissive and enmeshed attachment mediated associations of antipathy with paranoid and schizotypal PD traits. Enmeshed attachment mediated associations of role reversal with paranoid and schizotypal PD traits. Conclusions Attachment theory can inform lifespan models of how adverse developmental environments may increase the risk for psychosis. Insecure attachment provides a promising mechanism for understanding the development of schizophrenia-spectrum phenomenology and may offer a useful target for prophylactic intervention

Correction: Identification of the key structural elements of a dihydropyrimidinone core driving toward more potent Hsp90 C-terminal inhibitors

Correction for 'Identification of the key structural elements of a dihydropyrimidinone core driving toward more potent Hsp90 C-terminal inhibitors' by S. Teracciano et al., Chem. Commun., 2016, 52, 12857–12860

How SARS-CoV-2 Infection Impacts the Management of Patients with Vulvar Cancer: Experience in a Third-Level Hospital of Southern Italy

: Background: Since February 2020, the spread of Coronavirus Disease 2019 (COVID-19) in Italy has induced the government to call for lockdown of any activity apart from primary needs, and changing the lives of each of us. All that has dramatically impacted the management of patients affected by cancer. Patients with vulvar cancer (VC) represent a particularly frail population because they are elderly and affected by multiple comorbidities. The aim of this study is to evaluate the clinical impact of the SARS-CoV-2 infection on VC patients in terms of delay or impossibility of carrying out the scheduled treatment. Methods: The medical records of patients affected by vulvar tumors, referred to "DAI Materno-Infantile" of AOU Federico II of Naples between February 2020 and January 2022 were retrospectively analyzed. The presence of a positive reverse transcription-polymerase chain reaction (RT-PCR) in nasopharyngeal swab defined the positivity to SARS-CoV-2. Results: Twenty-four patients with VC were analyzed and scheduled for treatment. The median age was 70.7 years (range: 59-80). Seven (29.2%) patients were diagnosed with SARS-CoV-2 infection: In three (42.8%) patients, the treatment was delayed with no apparent consequences, in four (57.2%), the treatment was delayed or changed due to cancer progression and, of these four, one died due to respiratory complications of COVID-19, and one died due to oncologic disease progression. Conclusion: COVID-19 caused, in most cases, significant delays in oncologic treatments and high mortality in our series of patients affected by VC

Phase II Trial of IL-12 Plasmid Transfection and PD-1 Blockade in Immunologically Quiescent Melanoma.

PurposeTumors with low frequencies of checkpoint positive tumor-infiltrating lymphocytes (cpTIL) have a low likelihood of response to PD-1 blockade. We conducted a prospective multicenter phase II trial of intratumoral plasmid IL-12 (tavokinogene telseplasmid; "tavo") electroporation combined with pembrolizumab in patients with advanced melanoma with low frequencies of checkpoint positive cytotoxic lymphocytes (cpCTL).Patients and methodsTavo was administered intratumorally days 1, 5, and 8 every 6 weeks while pembrolizumab (200 mg, i.v.) was administered every 3 weeks. The primary endpoint was objective response rate (ORR) by RECIST, secondary endpoints included duration of response, overall survival and progression-free survival. Toxicity was evaluated by the CTCAE v4. Extensive correlative analysis was done.ResultsThe combination of tavo and pembrolizumab was well tolerated with adverse events similar to those previously reported with pembrolizumab alone. Patients had a 41% ORR (n = 22, RECIST 1.1) with 36% complete responses. Correlative analysis showed that the combination enhanced immune infiltration and sustained the IL-12/IFNγ feed-forward cycle, driving intratumoral cross-presenting dendritic cell subsets with increased TILs, emerging T cell receptor clones and, ultimately, systemic cellular immune responses.ConclusionsThe combination of tavo and pembrolizumab was associated with a higher than expected response rate in this poorly immunogenic population. No new or unexpected toxicities were observed. Correlative analysis showed T cell infiltration with enhanced immunity paralleling the clinical activity in low cpCTL tumors

The Great Debate at 'Immunotherapy Bridge', Naples, December 5, 2019

As part of the 2019 Immunotherapy Bridge congress (December 4–5, Naples, Italy), the Great Debate session featured counterpoint views from leading experts on six topical issues in immunotherapy today. These were the use of chimeric antigen receptor T cell therapy in solid tumors, whether the Immunoscore should be more widely used in clinical practice, whether antibody-dependent cellular cytotoxicity is important in the mode of action of anticytotoxic T-lymphocyte-associated protein 4 antibodies, whether the brain is immunologically unique or just another organ, the role of microbiome versus nutrition in affecting responses to immunotherapy, and whether chemotherapy is immunostimulatory or immunosuppressive. Discussion of these important topics are summarized in this report