Synthesis and characterisation of a new benzamide-containing nitrobenzoxadiazole as a GSTP1-1 inhibitor endowed with high stability to metabolic hydrolysis

The antitumor agent 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexan-1-ol (1) is a potent inhibitor of GSTP1-1, a glutathione S-transferase capable of inhibiting apoptosis by binding to JNK1 and TRAF2. We recently demonstrated that, unlike its parent compound, the benzoyl ester of 1 (compound 3) exhibits negligible reactivity towards GSH, and has a different mode of interaction with GSTP1-1. Unfortunately, 3 is susceptible to rapid metabolic hydrolysis. In an effort to improve the metabolic stability of 3, its ester group has been replaced by an amide, leading to N-(6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexyl)benzamide (4). Unlike 3, compound 4 was stable to human liver microsomal carboxylesterases, but retained the ability to disrupt the interaction between GSTP1-1 and TRAF2 regardless of GSH levels. Moreover, 4 exhibited both a higher stability in the presence of GSH and a greater cytotoxicity towards cultured A375 melanoma cells, in comparison with 1 and its analog 2. These findings suggest that 4 deserves further preclinical testing

MR breast imaging: A comparative analysis of conventional and parallel imaging acquisition [RM delle mammelle: Confronto tra tecnica convenzionale ed imaging parallelo]

Purpose. The objective of this study was to compare conventional breast magnetic resonance imaging (MRI) with breast MRI acquired with the sensitivity-encoding (SENSE) technique on a 1.5-T MRI scanner in the same patient, on the basis of image quality and kinetics analysis. Materials and methods. Thirty-one patients with suspicious mammography and US findings were included in the study. Conventional breast MRI consisted of the following sequences: T1 (matrix, 288x512); T2 (matrix 225x512); short tau inversion recovery (STIR) (matrix 320x224) and dynamic T1 [2D fast-field echo (FFE)] (matrix 256x512; temporal resolution =80 s). The SENSE technique included the following sequences: T1 (matrix 512x512); T2 (matrix 512x512); short-tau inversion recovery (STIR) (matrix 320x224); dynamic T1 (3D FFE) (matrix 512x512, with a temporal resolution ≤70 s). Image quality was graded on a four-point scale, and the mean scores given to each sequence were compared between the two protocols. The relative enhancement rates and the qualitative features of the signal intensity (SI)/time curves were also compared between the two protocols. Results. The readers found 64 contrast-enhanced lesions in 31 patients. Nineteen patients had a total of 27 malignant lesions. In the remaining 12 patients, 37 benign lesions were found. No significant differences between the two protocols were observed with regard to the mean relative enhancement rates and the qualitative features of the SI/time curves. In detail, the mean image quality scores were higher for SENSE imaging (p<0.05). The mean image quality score for the T1 and T2 morphological sequences were comparable. In contrast, the quality scores for the STIR images differed significantly between the two protocols (p<0.001), and a significant difference was also observed when comparing the T1 postcontrast images (p<0.001). Conclusions. Our data suggest that the SENSE imaging protocol applied in our study is superior to conventional imaging with regard to image quality, especially for T1 postcontrast and STIR images. SENSE imaging protocols may provide an alternative to conventional sequences for contrast-enhanced MRI of the breast using 1.5-T MR scanners. © 2008 Springer-Verlag

Desarrollo vegetativo y reproductivo de vástagos de diferente orden de tres híbridos comerciales de maíz en dos densidades de siembra

21-32La producción de macollos puede otorgar estabilidad al rendimiento del maíz en ambientes con oferta variable de recursos, o compensar fallas en el establecimiento de plántulas. El objetivo de este trabajo fue analizar la fenología de los estadios vegetativos y reproductivos de vástagos principales y macollos y su relación con el crecimiento en etapas tempranas del cultivo, en escenarios de alta oferta de recursos bajo densidades de siembra contrastantes. Se realizó un experimento a campo en la FA-UBA durante 2014-2015, con dos híbridos dentados (ARV2194HXRR y ARV2183MGRR) y un híbrido pisingallo (Argenpop 141) sembrados en dos densidades (3 y 6 plantas m-2) sin limitaciones hídrico-nutricionales. Desde etapas tempranas del ciclo, la proporción de plantas con macollos presentó diferencias (0,005 menor a P menor a 0.1) entre densidades (mayor en baja densidad). En ARV2194HXRR y Argenpop141, esta proporción respondió positiva y linealmente a la tasa de crecimiento del vástago principal durante los primeros 42 días desde emergencia. Para similares tasas, el ARV2183MGRR nunca presentó macollos. Debido a la mayor producción de macollos en baja densidad, ARV2194HXRR y Argenpop141 presentaron estabilidad en el número de vástagos m-2 (ca. 7,6 y 8,3 vástagos m-2 para ARV2194HXRR y Argenpop141; respectivamente) entre densidades. A pesar del menor número de hojas (ca. 13,8 vs 22 y 10,4 vs 18 hojas para macollos y vástagos principales de ARV2194HXRR y Argenpop141; respectivamente) y similar filocrono (ca. 44,6 y 56,5 °Cd hoja-1 para ARV2194HXRR y Argenpop141; respectivamente), los macollos florecieron más tardíamente (ca. 120 y 70 °Cd para ARV2194HXRR y Argenpop141; respectivamente) y presentaron una mayor asincronía floral (ca. -123 y -71°Cd para ARV2194HXRR y Argenpop141; respectivamente) que el vástago principal (ca. 18 y 7°Cd para ARV2194HXRR y Argenpop141; respectivamente), probablemente debido a la demora en el inicio del macollaje (aprox. en 8-9 hojas aparecidas del vástago principal) y en la iniciación floral de sus ápices

The Use of Artificial Intelligence (AI) in the Radiology Field: What Is the State of Doctor–Patient Communication in Cancer Diagnosis?

Simple Summary Artificial Intelligence (AI) has been increasingly used in radiology to improve diagnostic procedures over the past decades. The application of AI at the time of cancer diagnosis also creates challenges in the way doctors should communicate the use of AI to patients. The present systematic review deals with the patient's psycho-cognitive perspective on AI and the interpersonal skills between patients and physicians when AI is implemented in cancer diagnosis communication. Evidence from the retrieved studies pointed out that the use of AI in radiology is negatively associated with patient trust in AI and patient-centered communication in cancer disease. Background: In the past decade, interest in applying Artificial Intelligence (AI) in radiology to improve diagnostic procedures increased. AI has potential benefits spanning all steps of the imaging chain, from the prescription of diagnostic tests to the communication of test reports. The use of AI in the field of radiology also poses challenges in doctor-patient communication at the time of the diagnosis. This systematic review focuses on the patient role and the interpersonal skills between patients and physicians when AI is implemented in cancer diagnosis communication. Methods: A systematic search was conducted on PubMed, Embase, Medline, Scopus, and PsycNet from 1990 to 2021. The search terms were: ("artificial intelligence" or "intelligence machine") and "communication" "radiology" and "oncology diagnosis". The PRISMA guidelines were followed. Results: 517 records were identified, and 5 papers met the inclusion criteria and were analyzed. Most of the articles emphasized the success of the technological support of AI in radiology at the expense of patient trust in AI and patient-centered communication in cancer disease. Practical implications and future guidelines were discussed according to the results. Conclusions: AI has proven to be beneficial in helping clinicians with diagnosis. Future research may improve patients' trust through adequate information about the advantageous use of AI and an increase in medical compliance with adequate training on doctor-patient diagnosis communication

Characterization of Sirtuin Inhibitors in Nematodes Expressing a Muscular Dystrophy Protein Reveals Muscle Cell and Behavioral Protection by Specific Sirtinol Analogues

n/

RIP1-HAT1-SirT complex identification and targeting in treatment and prevention of cancer

Purpose: Alteration in cell death is a hallmark of cancer. A functional role regulating survival, apoptosis, and necroptosis has been attributed to RIP1/3 complexes.Experimental Design: We have investigated the role of RIP1 and the effects of MC2494 in cell death induction, using different methods as flow cytometry, transcriptome analysis, immunoprecipitation, enzymatic assays, transfections, mutagenesis, and in vivo studies with different mice models.Results: Here, we show that RIP1 is highly expressed in cancer, and we define a novel RIP1/3-SIRT1/2-HAT1/4 complex. Mass spectrometry identified five acetylations in the kinase and death domain of RIP1. The novel characterized pan-SIRT inhibitor, MC2494, increases RIP1 acetylation at two additional sites in the death domain. Mutagenesis of the acetylated lysine decreases RIP1-dependent cell death, suggesting a role for acetylation of the RIP1 complex in cell death modulation. Accordingly, MC2494 displays tumor-selective potential in vitro, in leukemic blasts ex vivo, and in vivo in both xenograft and allograft cancer models. Mechanistically, MC2494 induces bona fide tumor-restricted acetylated RIP1/caspase-8-mediated apoptosis. Excitingly, MC2494 displays tumor-preventive activity by blocking 7,12-dimethylbenz(α)anthracene-induced mammary gland hyperproliferation in vivoConclusions: These preventive features might prove useful in patients who may benefit from a recurrence-preventive approach with low toxicity during follow-up phases and in cases of established cancer predisposition. Thus, targeting the newly identified RIP1 complex may represent an attractive novel paradigm in cancer treatment and prevention

Targeting lysine deacetylases (KDACs) in parasites

Due to an increasing problem of drug resistance among almost all parasites species ranging from protists to worms, there is an urgent need to explore new drug targets and their inhibitors to provide new and effective parasitic therapeutics. In this regard, there is growing interest in exploring known drug leads of human epigenetic enzymes as potential starting points to develop novel treatments for parasitic diseases. This approach of repurposing (starting with validated targets and inhibitors) is quite attractive since it has the potential to reduce the expense of drug development and accelerate the process of developing novel drug candidates for parasite control. Lysine deacetylases (KDACs) are among the most studied epigenetic drug targets of humans, and a broad range of small-molecule inhibitors for these enzymes have been reported. In this work, we identify the KDAC protein families in representative species across important classes of parasites, screen a compound library of 23 hydroxamate- or benzamide-based small molecules KDAC inhibitors, and report their activities against a range of parasitic species, including the pathogen of malaria (Plasmodium falciparum), kinetoplastids (Trypanosoma brucei and Leishmania donovani), and nematodes (Brugia malayi, Dirofilaria immitis and Haemonchus contortus). Compound activity against parasites is compared to that observed against the mammalian cell line (L929 mouse fibroblast) in order to determine potential parasite-versus-host selectivity). The compounds showed nanomolar to sub-nanomolar potency against various parasites, and some selectivity was observed within the small panel of compounds tested. The possible binding modes of the active compounds at the different protein target sites within different species were explored by docking to homology models to help guide the discovery of more selective, parasite-specific inhibitors. This current work supports previous studies that explored the use of KDAC inhibitors in targeting Plasmodium to develop new anti-malarial treatments, and also pioneers experiments with these KDAC inhibitors as potential new anthelminthics. The selectivity observed begins to address the challenges of targeting specific parasitic diseases while limiting host toxicity

Regulatory Interplay between miR-181a-5p and Estrogen Receptor Signaling Cascade in Breast Cancer

he efficacy and side effects of endocrine therapy in breast cancer (BC) depend largely on estrogen receptor alpha (ERα) expression, the specific drug administered, and treatment scheduling. Although the benefits of endocrine therapy outweigh any adverse effects in the initial stages of BC, later- or advanced-stage tumors acquire resistance to treatments. The mechanisms underlying tumor resistance to therapy are still not well understood, posing a major challenge for BC patient care. Epigenetic regulation and miRNA expression may be involved in the switch from a treatment-sensitive to a treatment-resistant state and could provide a valid therapeutic strategy for ERα negative BC. Here, a hybrid lysine-specific histone demethylase inhibitor, MC3324, displaying selective estrogen receptor down-regulator-like activities in BC, was used to highlight the interplay between epigenetic and ERα signaling. MC3324 anticancer action is mediated by microRNA (miRNA) expression regulation, indicating an innovative function for this molecule. Integrated analysis suggests a crosstalk between estrogen signaling, ERα interactors, miRNAs, and their putative targets. Specifically, miR-181a-5p expression is regulated by MC3324 and has an impact on cellular levels of ERα. A comparison of breast tumor versus healthy mammary tissues confirmed the important role of miR-181a-5p in ERα regulation and points to its putative predictive function in BC therapy

Complete removal of the lesion as a guidance in the management of patients with breast ductal carcinoma in Situ

Background: Considering highly selected patients with ductal carcinoma in situ (DCIS), active surveillance is a valid alternative to surgery. Our study aimed to show the reliability of post-biopsy complete lesion removal, documented by mammogram, as additional criterion to select these patients. Methods: A total of 2173 vacuum‐assisted breast biopsies (VABBs) documented as DCIS were reviewed. Surgery was performed in all cases. We retrospectively collected the reports of post‐ VABB complete lesion removal and the histological results of the biopsy and surgery. We calculated the rate of upgrade of DCIS identified on VABB upon excision for patients with post‐biopsy complete lesion removal and for those showing residual lesion. Results: We observed 2173 cases of DCIS: 408 classified as low‐grade, 1262 as intermediate‐grade, and 503 as high‐grade. The overall upgrading rate to invasive carcinoma was 15.2% (330/2173). The upgrade rate was 8.2% in patients showing mammographically documented complete removal of the lesion and 19% in patients without complete removal. Conclusion: The absence of mammographically documented residual lesion following VABB was found to be associated with a lower upgrading rate of DCIS to invasive carcinoma on surgical excision and should be considered when deciding the proper management DCIS diagnosis

PARP-1 modulates amyloid beta peptide-induced neuronal damage.

Amyloid beta peptide (A beta) causes neurodegeneration by several mechanisms including oxidative stress, which is known to induce DNA damage with the consequent activation of poly (ADP-ribose) polymerase (PARP-1). To elucidate the role of PARP-1 in the neurodegenerative process, SH-SY5Y neuroblastoma cells were treated with A beta(25-35) fragment in the presence or absence of MC2050, a new PARP-1 inhibitor. A beta(25-35) induces an enhancement of PARP activity which is prevented by cell pre-treatment with MC2050. These data were confirmed by measuring PARP-1 activity in CHO cells transfected with amylod precursor protein and in vivo in brains specimens of TgCRND8 transgenic mice overproducing the amyloid peptide. Following A beta(25-35) exposure a significant increase in intracellular ROS was observed. These data were supported by the finding that A beta(25-35) induces DNA damage which in turn activates PARP-1. Challenge with A beta(25-35) is also able to activate NF-kB via PARP-1, as demonstrated by NF-kB impairment upon MC2050 treatment. Moreover, A beta(25-35) via PARP-1 induces a significant increase in the p53 protein level and a parallel decrease in the anti-apoptotic Bcl-2 protein. These overall data support the hypothesis of PARP-1 involvment in cellular responses induced by A beta and hence a possible rationale for the implication of PARP-1 in neurodegeneration is discussed