Pyrrolyl and Indolyl α-γ-Diketo Acid Derivatives Acting as Selective Inhibitors of Human Carbonic Anhydrases IX and XII.

Solid tumors are active tissues containing hypoxic regions and producing metabolic acids. By decreasing pH, cancer cells create a hostile environment for surrounding host cells and foster tumor growth and progression. By governing acid/base regulation, carbonic anhydrases (CAs) are involved in several physiological/pathological processes, including tumors. Indeed, CAs are clinically relevant in cancer therapy as among the fifteen human isoforms, two of them, namely CA IX (overexpressed in solid tumors and associated with increased metastasis and poor prognosis) and CA XII (overexpressed in some tumors) are involved in tumorigenesis. Targeting these two isoforms is considered as a pertinent approach to develop new cancer therapeutics. Several CA inhibitors (CAIs) have been described, even though they are unselective inhibitors of different isoforms. Thus, efforts are needed to find new selective CAIs. In this work, we described new diketo acid derivatives as CAIs, with the best acting compounds 1c and 5 as nanomolar inhibitors of CA IX and XII, being also two orders of magnitude selective over CAs I and II. Molecular modeling studies showed the different binding poses of the best acting CAIs within CA II and IX, highlighting the key structural features that could confer the ability to establish specific interactions within the enzymes. In different tumor cell lines overexpressing CA IX and XII, the tested compounds showed antiproliferative activity already at 24 h treatment, with no effects on somatic not transformed cells.

Preventing falls: the use of machine learning for the prediction of future falls in individuals without history of fall.

Nowadays, it becomes of paramount societal importance to support many frail-prone groups in our society (elderly, patients with neurodegenerative diseases, etc.) to remain socially and physically active, maintain their quality of life, and avoid their loss of autonomy. Once older people enter the prefrail stage, they are already likely to experience falls whose consequences may accelerate the deterioration of their quality of life (injuries, fear of falling, reduction of physical activity). In that context, detecting frailty and high risk of fall at an early stage is the first line of defense against the detrimental consequences of fall. The second line of defense would be to develop original protocols to detect future fallers before any fall occur. This paper briefly summarizes the current advancements and perspectives that may arise from the combination of affordable and easy-to-use non-wearable systems (force platforms, 3D tracking motion systems), wearable systems (accelerometers, gyroscopes, inertial measurement units-IMUs) with appropriate machine learning analytics, as well as the efforts to address these challenges.

Reply to "Describing center of pressure movement in stabilometry by ellipse area approximation" from Agnieszka Golab concerning the paper "A Review of Center of Pressure (COP) Variables to Quantify Standing Balance in Elderly People: Algorithms and Open Access Code".

Letter to the Editor concerning "Describing center of pressure movement in stabilometry by ellipse area approximation" from Agnieszka Golab.

The kinesin Eg5 inhibitor K858 exerts antiproliferative and proapoptotic effects and attenuates the invasive potential of head and neck squamous carcinoma cells.

Our group recently demonstrated that K858, an inhibitor of motor kinesin Eg5, has important antiproliferative and apoptotic effects on breast cancer, prostatic cancer, melanoma and glioblastoma cells. Since high levels of kinesin Eg5 expression have been correlated with a poor prognosis in laryngeal carcinoma, we decided to test the anticancer activity of K858 toward this tumor, which belongs to the group of head and neck squamous cell carcinomas (HNSCCs). These cancers are characterized by low responsiveness to therapy. The effects of K858 on the proliferation and assembly of mitotic spindles of three human HNSCC cell lines were studied using cytotoxicity assays and immunofluorescence for tubulin. The effect of K858 on the cell cycle was analyzed by FACS. The expression levels of cyclin B1 and several markers of apoptosis and invasion were studied by Western blot. Finally, the negative regulation of the malignant phenotype by K858 was evaluated by an invasion assay. K858 inhibited cell replication by rendering cells incapable of developing normal bipolar mitotic spindles. At the same time, K858 blocked the cell cycle in the G2 phase and induced the accumulation of cytoplasmic cyclin B and, eventually, apoptosis. Additionally, K858 inhibited cell migration and attenuated the malignant phenotype. The data described confirm that kinesin Eg5 is an interesting target for new anticancer strategies and suggest that this compound may be a powerful tool for an alternative therapeutic approach to HNSCCs.

A review of center of pressure (COP) variables to quantify standing balance in elderly people: Algorithms and open-access code.

Postural control is often quantified by recording the trajectory of the center of pressure (COP)-also called stabilogram-during human quiet standing. This quantification has many important applications, such as the early detection of balance degradation to prevent falls, a crucial task whose relevance increases with the aging of the population. Due to the complexity of the quantification process, the analyses of sway patterns have been performed empirically using a number of variables, such as ellipse confidence area or mean velocity. This study reviews and compares a wide range of state-of-the-art variables that are used to assess the risk of fall in elderly from a stabilogram. When appropriate, we discuss the hypothesis and mathematical assumptions that underlie these variables, and we propose a reproducible method to compute each of them. Additionally, we provide a statistical description of their behavior on two datasets recorded in two elderly populations and with different protocols, to hint at typical values of these variables. First, the balance of 133 elderly individuals, including 32 fallers, was measured on a relatively inexpensive, portable force platform (Wii Balance Board, Nintendo) with a 25-s open-eyes protocol. Second, the recordings of 76 elderly individuals, from an open access database commonly used to test static balance analyses, were used to compute the values of the variables on 60-s eyes-open recordings with a research laboratory standard force platform.

Anti-Tumoral Effects of a (1H-Pyrrol-1-yl)Methyl-1H-Benzoimidazole Carbamate Ester Derivative on Head and Neck Squamous Carcinoma Cell Lines.

Nocodazole is an antineoplastic agent that exerts its effects by depolymerizing microtubules. Herein we report a structural analog of nocodazole, a (1H-pyrrol-1-yl)methyl-1H-benzoimidazole carbamate ester derivative, named RDS 60. We evaluated the antineoplastic properties of RDS 60 in two human head and neck squamous cell carcinoma (HNSCC) cell lines and we found that this compound significantly inhibited replication of both HNSCC cell lines without inducing any important cytotoxic effect on human dermal fibroblasts and human keratinocytes. The treatment of HNSCC cell lines with 1 µM RDS 60 for 24 h stopped development of normal bipolar mitotic spindles and, at the same time, blocked the cell cycle in G2/M phase together with cytoplasmic accumulation of cyclin B1. Consequently, treatment with 2 µM RDS 60 for 24 h induced the activation of apoptosis in both HNSCC cell lines. Additionally, RDS 60 was able to reverse the epithelial-mesenchymal transition and to inhibit cell migration and extracellular matrix infiltration of both HNSCC cell lines. The reported results demonstrate that this compound has a potent effect in blocking cell cycle, inducing apoptosis and inhibiting cell motility and stromal invasion of HNSCC cell lines. Therefore, the ability of RDS 60 to attenuate the malignancy of tumor cells suggests its potential role as an interesting and powerful tool for new approaches in treating HNSCC.

The 5P program, personalized and participatory primary prevention pathway: Rational and design of a clinical trial in general practice.

The aging of the population is leading to an increase in the number of people with loss of autonomy, placing a strain on the health care system. Its prevention at early stages such as the frailty stage would allow an improvement in the quality of life of seniors while limiting health care expenses. The "Atout Age" prevention program set up by the health public authorities of Reunion Island for retired people and the new frailty assessment tools based on mathematical machine learning algorithms could improve the ambulatory care of senior citizens. At present, referral care remains hospital with comprehensive geriatric assessment and there is a lack of evidence of the effectiveness of a prevention pathway for loss of autonomy in primary care. For these reasons, the 5P program "Personalized and Participative Primary Prevention Pathway" has been started in order to obtain scientific evidence. In this article, we present the objectives, design and first results, used in the 5P program up to the implementation of a clinical trial in general practice. The program is articulated in 3 phases. A first phase to evaluate the acceptability of innovative screening tools for frailty. A second pilot phase evaluates the feasibility of a large-scale ambulatory clinical trial in general practice. The last phase described in this article, is a multisite, pseudo-randomized, controlled clinical trial measuring the impact of the "Atout Age" workshops on the physical performance and the quality of life of seniors compared with their usual ambulatory follow-up.

Design, Synthesis and Biological Evaluation of New Pyrimidine Derivatives as Anticancer Agents.

BACKGROUND: Anticancer drug resistance is a challenging phenomenon of growing concern which arises from alteration in drug targets. Despite the fast speed of new chemotherapeutic agent design, the increasing prevalence of this phenomenon requires further research and treatment development. Recently, we reported a new aminopyrimidine compound-namely RDS 344-as a potential innovative anticancer agent. METHODS: Herein, we report the design, synthesis, and anti-proliferative activity of new aminopyrimidine derivatives structurally related to RDS 3442 obtained by carrying out substitutions at position 6 of the pyrimidine core and/or on the 2-aniline ring of our hit. The ability to inhibit cell proliferation was evaluated on different types of tumors, glioblastoma, triple-negative breast cancer, oral squamous cell carcinomas and colon cancer plus on human dermal fibroblasts chosen as control of normal cells. RESULTS: The most interesting compound was the N-benzyl counterpart of RDS 3442, namely 2a, that induced a significant decrease in cell viability in all the tested tumor cell lines, with EC50s ranging from 4 and 8 µM, 4-13 times more active of hit. CONCLUSIONS: These data suggest a potential role for this class of molecules as promising tool for new approaches in treating cancers of different histotype.

A Langevin-Based Model With Moving Posturographic Target to Quantify Postural Control.

Falls are a major concern of public health, particularly for older adults, as the consequences of falls include serious injuries and death. Therefore, the understanding and evaluation of postural control is considered key, as its deterioration is an important risk factor predisposing to falls. In this work we introduce a new Langevin-based model, local recall, that integrates the information from both the center of pressure (CoP) and the center of mass (CoM) trajectories, and compare its accuracy to a previously proposed model that only uses the CoP. Nine healthy young participants were studied under quiet bipedal standing conditions with eyes either open or closed, while standing on either a rigid surface or a foam. We show that the local recall model produces significantly more accurate prediction than its counterpart, regardless of the eyes and surface conditions, and we replicate these results using another publicly available human dataset. Additionally, we show that parameters estimated using the local recall model are correlated with the quality of postural control, providing a promising method to evaluate static balance. These results suggest that this approach might be interesting to further extend our understanding of the underlying mechanisms of postural control in quiet stance.

Oxidative Stress and Inflammation Biomarker Expression in Obstructive Sleep Apnea Patients.

Obstructive Sleep Apnea Syndrome (OSAS) is a respiratory sleep disorder characterised by repeated episodes of partial or complete obstruction of the upper airway during the night. This obstruction usually occurs with a reduction (hypopnea) or complete cessation (apnea) of the airflow in the upper airways with the persistence of thoracic-diaphragmatic respiratory movements. During the hypopnea/apnea events, poor alveolar ventilation reduces the oxygen saturation in the arterial blood (SaO2) and a gradual increase in the partial arterial pressure of carbon dioxide (PaCO2). The direct consequence of the intermittent hypoxia is an oxidative imbalance, with reactive oxygen species production and the inflammatory cascade's activation with pro and anti-inflammatory cytokines growth. Tumour necrosis factors, inflammatory cytokines (IL2, IL4, IL6), lipid peroxidation, and cell-free DNA have been found to increase in OSAS patients. However, even though different risk-related markers have been described and analysed in the literature, it has not yet been clarified whether specified inflammatory bio-markers better correlates with OSAS diagnosis and its clinical evolution/comorbidities. We perform a scientific literature review to discuss inflammatory and oxidative stress biomarkers currently tested in OSAS patients and their correlation with the disease's severity and treatment.

Tissue Expression of Androgen Receptor Splice Variant 7 at Radical Prostatectomy Predicts Risk of Progression in Untreated Nonmetastatic Prostate Cancer.

BACKGROUND: Androgen receptor splice variant V7 (AR-V7) was recently detected in circulating tumor cells of castration-resistant prostate cancer (PC) patients and its expression correlated with resistance to new-generation androgen signaling inhibitors. OBJECTIVES: We retrospectively analyzed whether AR-V7 expression was detectable on radical prostatectomy (RP) specimens of untreated nonmetastatic PC cases, and whether it could be associated with progression after surgery. METHOD: The expression of AR-V7 and AR-FL (full length) was separately evaluated by immunohistochemistry using a streptavidin-biotin-peroxidase system with 2 anti-AR-V7 and anti-AR-FL rabbit monoclonal antibodies. RESULTS: 56 PC cases, classified by their clinical risk, were analyzed. Positive expression was found in 24/32 cases in the high-risk group, 4/13 in the intermediate-risk group, and only 2/11 in the low-risk group. We found a significant correlation between AR-V7 positivity and both risk classification (p < 0.001) and progression after surgery (p < 0.001). CONCLUSIONS: In our population of untreated nonmetastatic PC, AR-V7 is detectable by immunohistochemistry in more than 50% of cases. At this early stage, AR-V7 positivity is associated with risk classification and it can predict progression after surgery.

Discovery of a pyrimidine compound endowed with antitumor activity.

Recently, some synthetic nitrogen-based heterocyclic molecules, such as PJ34, have shown pronounced antitumor activity. Therefore, we designed and synthesized new derivatives characterized by a nitrogen-containing scaffold and evaluated their antiproliferative properties in tumor cells. We herein report the effects of three newly synthesized compounds on cell lines from three different human cancers: triple-negative breast cancer, colon carcinoma and glioblastoma. We found that two of these compounds did not affect proliferation, while the third significantly inhibited replication of the three cell lines. Moreover, this third molecule at 20 µM led to the upregulation of p21 and p27 and blockage of the cell cycle at G0/G1; in addition, it induced apoptosis in all three cell lines when used at higher concentrations (30-50 µM). The results demonstrate that this compound is a potent inhibitor of replication, an inducer of apoptosis and a negative regulator of cell cycle progression for cancer cells of different histotypes. Our data suggest a potential role for this new molecule as an interesting and powerful tool for new approaches in treating various cancers.

Dissecting the role of novel EZH2 inhibitors in primary glioblastoma cell cultures: effects on proliferation, epithelial-mesenchymal transition, migration, and on the pro-inflammatory phenotype.

BACKGROUND: Glioblastoma (GBM) is the most lethal and aggressive malignant primary brain tumor in adults. After surgical resection of the tumor, the patient typically should be subjected to chemotherapy (temozolomide, TMZ) and concomitant radiotherapy. Since the TMZ treatment does not lead to complete remission and often develops resistance, the identification of efficacious therapeutics is strongly to pursue. Among the epigenetic players, the H3K27 methyltransferase (MT) EZH2 (enhancer of zeste homologue 2) has been found overexpressed or mutated in several human cancers including gliomas, and its overexpression is associated with poor outcome in GBM. Two EZH2 inhibitors (EZH2i), UNC1999 and GSK343, suppressed GBM growth in vitro and in vivo indicating that EZH2i can be potential drugs against GBM. RESULTS: Two new EZH2i, MC4040 and MC4041, were designed, prepared, and tested by us to determine their effects in primary GBM cell cultures. MC4040 and MC4041 displayed single-digit micromolar inhibition of EZH2, 10-fold less potency against EZH1, and no activity towards other MTs. In primary GBM cells as well as in U-87 GBM cells, the two compounds reduced H3K27me3 levels, and dose- and time-dependently impaired GBM cell viability without inducing apoptosis and arresting the cell cycle in the G0/G1 phase, with increased p21 and p27 levels. In combination with TMZ, MC4040 and MC4041 displayed stronger, but not additive, effects on cell viability. The potent clinical candidate as EZH2i tazemetostat, alone or in combination with TMZ, exhibited a similar potency of inhibition of GBM cell growth when compared to MC4040 and MC4041. At the molecular level, MC4040 and MC4041 reduced the VEGFR1/VEGF expression, reversed the epithelial-mesenchymal transition (EMT), and hampered cell migration and invasion attenuating the cancer malignant phenotype. Treatment of GBM cells with MC4040 and MC4041 also impaired the GBM pro-inflammatory phenotype, with a significant decrease of TGF-ß, TNF-α, and IL-6, joined to an increase of the anti-inflammatory cytokine IL-10. CONCLUSIONS: The two novel EZH2i MC4040 and MC4041 impaired primary GBM cell viability, showing even stronger effects in combination with TMZ. They also weakened the aggressive malignant phenotype by reducing angiogenesis, EMT, cell migration/invasion and inflammation, thus they may be considered potential candidates against GBM also for combination therapies.

Francesco Durante and the First Intracranial Tumor Successfully Operated on with Long Survival (1884).

Francesco Durante was born in Sicily, precisely Letojanni Gallodoro. He contributed to the history of neurosurgery in not only Italy but the whole world. In June 1884, he removed a left frontal meningioma, describing a personal technique of craniotomy with a discontinuous osteotangential section flap. It was the first such operation to be performed in any country after which the patient had a long survival. The important and pioneering contribution made by Durante to the history of neurosurgery is testified by his Treaty on Pathology and Surgical Therapy. Durante's procedure for craniotomy remained the best for several years. His contributions are still valid in medicine today, within not only the neurosurgical community but also other surgical disciplines, because he also developed innovative practices in the fields of oncology, general surgery, and orthopedics in addition to designing special surgical instruments.

Estimating Center of Mass Trajectory in Quiet Standing: a Review.

As falls prevalence increases with the aging of the population, early detection of balance degradation is of great importance for efficient prevention and treatment. This work compares a wide range of state-of-the-art methods to estimate the trajectory of the center of mass - a key aspect of postural control quantification. This comparison is done through multiple complementary metrics over a large dataset, highlighting the pros and cons of each method as well as the key influence of the data preprocessing. Additionally, we introduce several improvements and parameter tunings for these methods that increase their accuracy or reduce contextual information requirement.