An ingestible capsule for the photodynamic therapy of helicobacter pylori infection

Helicobacter pylori (H. pylori) is a Gram-negative pathogen bacterium affecting the mucosa of the stomach and causing severe gastric diseases. H. pylori-related infections are currently treated with pharmacological therapies, which are associated with increasing antibiotic resistance and consequent reduction of the efficacy down to 70%-85%. Moreover, drugs have generally side effects that further affect the healthcare system in terms of additional financial and medical efforts. The aim of this study is to present an innovative device for the treatment of H. pylori infection, consisting of an ingestible lighting capsule performing photodynamic therapy by means of light at specific wavelengths. The proposed treatment is minimally invasive and the described system can be considered the first photodynamic swallowable device ever proposed. Preliminary experiments demonstrated that the capsule integrated with LED sources can provide the required lighting power to kill the bacterium with an efficiency up to about 96%

Correlations between Molecular Alterations, Histopathological Characteristics, and Poor Prognosis in Esophageal Adenocarcinoma

Esophageal adenocarcinoma (EAC) is a severe malignancy with increasing incidence, poorly understood pathogenesis, and low survival rates. We sequenced 164 EAC samples of naïve patients (without chemo-radiotherapy) with high coverage using next-generation sequencing technologies. A total of 337 variants were identified across the whole cohort, with TP53 as the most frequently altered gene (67.27%). Missense mutations in TP53 correlated with worse cancer-specific survival (log-rank p = 0.001). In seven cases, we found disruptive mutations in HNF1alpha associated with other gene alterations. Moreover, we detected gene fusions through massive parallel sequencing of RNA, indicating that it is not a rare event in EAC. In conclusion, we report that a specific type of TP53 mutation (missense changes) negatively affected cancer-specific survival in EAC. HNF1alpha was identified as a new EAC-mutated gen

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Prompt-engineering for lie detection using FLANT-T5 and ChatGPT

openDiversi studi evidenziano che l’accuratezza degli esseri umani nell’identificare la menzogna non è significativamente superiore alla probabilità di andare a caso (50%). Pertanto, nuovi studi si sono focalizzati sull’uso di tecniche di Machine Learning e Deep Learning al fine di raggiungere livelli di accuratezza superiori. Loconte et al. (2023b), in uno studio under review, hanno esplorato per la prima volta le prestazioni di un Large Language Model (LLM), nel caso di specie FLAN-T5, in un compito di classificazione applicato al contesto della lie detection. A tal scopo, gli autori hanno utilizzato la tecnica del fine-tuning, che consiste nell'ottimizzare i parametri di un LLM pre-addestrato su un compito specifico o su un dataset ad-hoc, migliorando notevolmente la capacità del LLM di generare risposte coerenti in relazione agli obiettivi predisposti. Una tecnica alternativa al fine-tuning che permette di migliorare l’allineamento tra le richieste dell’utente e le risposte di un LLM è quella del prompt-engineering, ovvero manipolare e cercare i prompt (i.e., le istruzioni) che garantiscono la migliore performance. All’interno delle più semplici e diffuse strategie di prompting rientrano: zero-shot prompting, quando la richiesta di un utente posta a un LLM è priva di informazioni circa il contesto specifico o priva di esempi, e la few-shot prompting, quando, la richiesta di un utente è seguita da pochi esempi su cui il LLM si ancora per fornire la sua risposta. In questo studio, l’obiettivo è quello di istruire due LLMs, in particolare FLAN-T5 e GPT-3.5, nel rilevamento della menzogna attraverso la tecnica del prompt-engineering. A tale scopo sono stati condotti tre esperimenti volti a testare diverse tipologie di prompt in un compito di classificazione della menzogna su tre dataset contenenti opinioni personali, ricordi autobiografici e intenzioni future. Nel primo esperimento, FLAN-T5 e GPT-3.5 sono stati testati utilizzando la tecnica zero-shot usando un prompt autogenerato da GPT-3.5. I risultati mostrano che sia FLAN-T5 che GPT-3.5 raggiungono livelli di accuratezza discreto solamente nel dataset delle opinioni personali, mentre non ottengono performance soddisfacenti negli altri due. Nel secondo esperimento si è cercato di migliorare l’accuratezza della performance di FLAN-T5 testando una strategia few-shot, ovvero utilizzando un prompt che contenesse un certo numero di esempi (inizialmente 5 e poi 10). Inoltre, è stato testato come l’uso di diverse parole chiave nell’output (“true/false”; “honest/dishonest”; “truthful/deceptive”) potesse inficiare l’accuratezza finale. Infine, nel terzo esperimento, considerando i risultati soddisfacenti ottenuti da GPT-3.5 con la strategia zero-shot, si è tentato di manipolare il contesto mediante l’utilizzo dell’impostazione personalizzata di GPT-3.5, nota come custom instruction

Identification of molecular biomarkers in esophageal adenocarcinoma

Esophageal adenocarcinoma (EAC) is a severe cancer that has been on the rise in Western nations over the past few decades. It has a high mortality rate and the 5-year survival rate is only 35%–45%. EAC has been included in a group of tumors with one of the highest rates of copy number alterations (CNAs), somatic structural rearrangements, high mutation frequency, with different mutational signatures, and with epigenetic mechanisms. The vast heterogeneity of EAC mutations makes it challenging to comprehend the biology that underlies tumor onset and development, identify prognostic biomarkers, and define a molecular classification to stratify patients. The only way to resolve the current disagreements is through an exhaustive molecular analysis of EAC. We examined the genetic profile of 164 patients' esophageal adenocarcinoma samples (without chemo-radiotherapy). The included patients did not receive neoadjuvant therapies, which can change the genetic and molecular composition of the tumor. Using next-generation sequencing technologies (NGS) at high coverage, we examined a custom panel of 26 cancer-related genes. Over the entire cohort, 337 variants were found, with the TP53 gene showing the most frequent alteration (67.27%). Poorer cancer-specific survival was associated with missense mutations in the TP53 gene (Log Rank P=0.0197). We discovered HNF1alpha gene disruptive mutations in 7 cases that were also affected by other gene changes. We started to investigate its role in EAC cell lines by silencing HNF1alpha to mimic our EAC cohort and we use Seahorse technique to analyze its role in the metabolism in esophageal cell. No significant changes were found in transfected cell lines. We conclude by finding that a particular class of TP53 mutations (missense changes) adversely impacted cancer-specific survival in EAC. HNF1alpha, a new EAC-mutated gene, was found, but more research is required to fully understand its function as a tumor suppressor gene

Omics Technologies Improving Breast Cancer Research and Diagnostics

Breast cancer (BC) has yielded approximately 2.26 million new cases and has caused nearly 685,000 deaths worldwide in the last two years, making it the most common diagnosed cancer type in the world. BC is an intricate ecosystem formed by both the tumor microenvironment and malignant cells, and its heterogeneity impacts the response to treatment. Biomedical research has entered the era of massive omics data thanks to the high-throughput sequencing revolution, quick progress and widespread adoption. These technologies—liquid biopsy, transcriptomics, epigenomics, proteomics, metabolomics, pharmaco-omics and artificial intelligence imaging—could help researchers and clinicians to better understand the formation and evolution of BC. This review focuses on the findings of recent multi-omics-based research that has been applied to BC research, with an introduction to every omics technique and their applications for the different BC phenotypes, biomarkers, target therapies, diagnosis, treatment and prognosis, to provide a comprehensive overview of the possibilities of BC research

Therapeutic potential of nvp‐bkm120 in human osteosarcomas cells

none8noOsteosarcoma (OS) is the most common pediatric malignant neoplasia of the skeletal system. It is characterized by a high degree of malignancy and a severe tendency to metastasize. In the past decade, many studies have provided evidence that the phosphoinositide 3-kinase (PI3K) signaling pathway is one of the most frequently altered pathways in human cancer, and has a critical role in driving tumor initiation and progression. Here, we have analyzed the therapeutic potential of the pan-PI3K inhibitor NVP-BKM120, which has recently entered clinical Phase II for treatment of PI3K-dependent cancers on three OS cell lines. We observed a concentration- and time-dependent decrease of Ser473 p-Akt as well as reduced levels of Thr37/46 p-4E-BP1, an indicator of the mammalian target of rapamycin complex 1 activity. All OS cell lines used in this study responded to BKM120 treatment with an arrest of cell proliferation, an increase in cell mortality, and an increase in caspase-3 activity. MG-63 cells were the most responsive cell line, demonstrating a significant increase in sub-G1 cells, and a rapid induction of cell death. Furthermore, we demonstrate that BKM120 is more effective when used in combination with other standard chemotherapeutic drugs. Combining BKM120 with vincristine demonstrated a more synergistic effect than BKM120 with doxorubicin in all the lines. Hence, we suggest that BKM120 may be a novel therapy for the treatment of OS presenting with anomalous upregulation of the PI3K signaling pathway.noneBavelloni, Alberto; Focaccia, Enrico; Piazzi, Manuela; Orsini, Arianna; Ramazzotti, Giulia; Cocco, Lucio; Blalock, William; Faenza, IreneBavelloni, Alberto; Focaccia, Enrico; Piazzi, Manuela; Orsini, Arianna; Ramazzotti, Giulia; Cocco, Lucio; Blalock, William; Faenza, Iren

Methadone Dose Adjustments, Plasma R-Methadone Levels and Therapeutic Outcome of Heroin Users: A Randomized Clinical Trial

AIMS: We aimed to improve the retention in treatment and therapeutic outcome of methadone maintenance treatment (MMT) patients by adjusting the oral methadone dose in order to reach a "target" plasma R-methadone level (80-250 ng/mL). METHODS: A multicenter randomized controlled trial was organized. RESULTS: The intention-to-treat statistical analysis showed that repeated dose adjustments performed in order to obtain therapeutic plasma R-methadone levels did not improve retention in treatment of heroin-dependent patients. However, patients having plasma methadone levels in the "target range" at the beginning of the study had a better retention in treatment than controls. Furthermore, patients succeeding in keeping plasma R-methadone target levels (per protocol analysis) remained in treatment and improved their social scores better than controls. -Conclusion: Although the primary endpoint of this study was not demonstrated, a post hoc and a per protocol analysis suggested that patients in MMT with plasma R-methadone concentrations in the target range have a better therapeutic outcome than controls