Early Evidences Research Articles

Alzheimer's disease: A role of biomarkers in early diagnosis and evidences from African ethnomedicinal knowledge.

Alzheimer's disease (AD) is a neurological ailment that primarily affects the elderly and necessitates an efficient treatment regimen backed up by extensive care. Despite advancement in the in vivo imaging techniques focussing on early diagnosis of reliable biomarkers using novel magnetic resonance imaging (MRI) and positron emission topography (PET) scans, AD remains largely unexplained and effective preventative and treatment strategies are still lacking. Consequently, research groups are constantly attempting to improve its early detection, using both invasive and non-invasive techniques with established core markers like Aβ and Tau (t-tau and p-tau) proteins. Unfortunately, African American and other black races are facing an increasing burden of closely associated risk factors, and only a few attempts have been made to find effective complementary and alternative therapies for AD cure and management. A greater epidemiology and natural product research are required to deal with the concurrent rise of dementia among quickly ageing African population, which so far have largely been ignored in addition to a disparity in the AD risk factors. We have tried to bring attention to the issue by reviewing up on this predisposition while generating a perspective on how race may affect AD risk and expression. This article also puts emphasis on finding new research leads from African phytodiversity while presenting several of the important species along with their biological agents found helpful in dementia related symptoms.

Determinants of the Human Development Index (HDI) in Indonesia, 2014 - 2021

Human development is a process of community change in improving the welfare andprosperity of their lives which includes aspects of health, education, economic andsocial aspects. This study aims to analyze the effect of protein intake, early marriage,health and educational facilities, unemployment, and MSMEs on HDI in Indonesia.The OLS and FEM model are used to estimate Indonesia’s 34 provinces panel dataset from 2014 in 2021. The study results show the life expectancy was affected byprotein consumption, number of hospitals, and health centers. The average length ofschooling is affected by the number of elementary, high school, and vocational schools and is influenced by the number of elementary and vocational school teachers. Gross Domestic Regional Product (GRDP) per capita is affected by unemployment rate and MSMEs. The increasing of protein consumption, early marriages evidences, number of health care provision, number of school are correlated on HDI. Furthermore, HDI is also affectef by the reduction of unemployment and number of MSMEs.

Abstract P4-07-23: Piezo1 is associated with worse prognosis along with promoted epithelial-mesenchymal transition and hypoxia as well as less anti-cancer immune cells in hormone receptor (HR)-negative breast cancer

Abstract Introduction: Piezo1 is a transmembrane protein, forming a mechano-sensitive ion channel. Piezo channels play an important role in mechano-sensing and mechano-transduction. Stretch activation of Piezo channels lead to influx of cations and activation of additional Ca2+ channels and depolarization. There are early evidences that Piezo1 channel signaling alters cancer cell behavior. It promotes migration in breast cancer cells, migration and chemo-resistance in gastric cancer cells, invasion of osteosarcoma cells, and enhances cell survival in synovial sarcoma cells. Contrary, lower level of Piezo1 associates with more invasive phenotype in lung cancer. In this study, we aimed to investigate clinical relevance of Piezo1 expression in breast cancer. Methods: In order to investigate Piezo1 clinical relevance in breast cancer patients, we used The Cancer Genome Atlas (TCGA) breast cancer cohort as a testing cohort, and GSE3494 as validation cohort. Piezo1 expression levels were compared among different stages as well as breast cancer subtypes. Patients’ survival was compared based on Piezo1 expression in each subtype. Gene set enrichment analysis (GSEA) and cibersort algorithms were used to evaluate pathways and infiltrating immune cells associated with PIEZO1 expression. Results: There was no significant difference in PIEZO1 expressions based on AJCC stage (P=0.258). PIEZO1 expression was significantly higher in the hormone receptor (HR)-negative (both estrogen receptor (ER)- and progesterone receptor (PR)-negative) tumors (P<0.001), whereas, there was no significant difference between HER2-positive and -negative tumors (P=0.279). When we compared patient survival based on PIEZO1 expression, there was no significant difference in the whole breast cancer cohort (disease-free survival (DFS); P=0.201, overall survival (OS); P=0.694). On the other hand, high PIEZO1 expression showed significantly worse prognosis for both DFS (P=0.033) and OS (P=0.002) in the HR-negative cohort, but not in HR-positive cohort (DFS; P=0.995, OS; P=0.083). These findings were validated in validation cohort GSE3494, in which PIEZO1 expression was higher in the HR-negative patients as compared to its counterpart (P=0.006) and higher PIEZO1 showed worse prognosis in the HR-negative cohort (P=0.003). As possible mechanisms, GSEA revealed that PIEZO1 high expression tumor was associated with cancer aggressiveness characteristics, such as epithelial-mesenchymal transition (EMT) (P<0.001) and hypoxia (P<0.001) in HR-negative breast cancer. Further, PIEZO1 high expressing tumor has less anti-cancer immune cells, including activated CD4+ memory T cells (P=0.020) and CD8+ T cells (P=0.002). Conclusion: We found that PIEZO1 high expression was associated with poor prognosis in HR-negative breast cancer patients. It may be due to promoted EMT and hypoxic condition, as well as less immunogenic characteristics. Citation Format: Eriko Katsuta, Kazuaki Takabe, Mateusz Opyrchal. Piezo1 is associated with worse prognosis along with promoted epithelial-mesenchymal transition and hypoxia as well as less anti-cancer immune cells in hormone receptor (HR)-negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-07-23.

Comparative aspects regarding concrete of structural grade made with recycled brick aggregate with / without fine particles from crushing

Recycled brick aggregate (RBA) is regarded like an eco-friendly aggregate because it contributes to conservation of the resources of natural aggregate. This type of aggregate may come from building construction waste, construction demolition waste (CDW) and ceramic industry waste. The RBA aggregate is obtained through crushing but a substantial percentage of the resulted particles are small in size being included in the fine aggregate category and its use is usually disregarded.Recycled brick aggregate concrete (RBAC) is a conventional making-concrete in which commonly the coarse and fine aggregate consist of coarse recycled brick particles and sand, respectively. Early evidences on RBAC are mentioned in the sixties of the last century in Germany, but many studies were developed after 2000. Nowadays, RBAC is regarded like a sustainable material having a positive environmental impact.This study assess feasibility of using fine particles of RBA obtained through crushing of brick waste from the buildings demolition in the conventional recycled brick aggregate concrete and its influence on some properties of RBAC like density and strength. As reference concrete, RBAC containing RBA aggregate as coarse and sand as fine aggregate was developed. Subsequently considering the same particles size distribution of aggregate, concrete mixes were developed in which each size of sand it was replaced in volume by fine brick aggregate (FBA) of equal size, size by size, until the entire replacement. For a valid comparison, the mix parameters like the water-to-cement ratio, cement content and volume of aggregate were identical for all mixes.The results indicate that replacing consecutively each size fraction of sand in conventional RBAC and thus increasing the replacement volume has in some extent influence on strength at standard testing ages. In this study, replacing entirely sand with fine brick aggregate the density and strength decreased with 150 kg/m3 and 17%, respectively.

Effectiveness of Structured Teaching Programme (STP) on knowledge Regarding Selected Minor Ailments of Newborn among Primipara Mothers Admitted in PNC ward, AIIMS Raipur

Newborn babies constitute the foundation of life. The birth of a baby is one of the most awe inspiring and emotional events that can occur in one’s life time. In India most the mothers are not aware of management regarding minor disorder of newborn (vomiting, diarrhea, physiological jaundice conjunctivitis, umbilical cord infection, skin rashes etc). Mother plays an important role in the identifying minor developmental deviation and early evidences of the disease process because she is constantly and closely watching her baby. Methodology: pre experimental (one group pretest and posttest) design was adopted for this study. The study was conducted at postnatal ward AIIMS Raipur with sample size of 30 primipara mothers. Non probability convenient sampling technique was adopted to select the sample. The data was collected by means of self-structured questionnaire to assess the knowledge among primipara mothers. Result: The mean score of pre-test was 15.36 and mean score of post-test was 22.4 and the mean improvement was 7.04, which is 45.83% of total primipara mothers. The paired ‘t’ value obtained for knowledge was 10.41 which was found significant at 0.05 level (p<0.05) which is 2.05. Which result shows that significantly an improvement in the knowledge of the primipara mothers after the structured teaching programme (STP) on selected minor ailments of newborn.

Epileptic seizures in patients with COVID-19: A systematic review of early evidences

Background: Global emergence of SARS-CoV-2 surfaced neurological complications amongst the patients. COVID-19 resembles with other coronavirus strains follows a trend of neurological complication, damage and encephalopathy, which entails considerable risks, requires attention for the neurologists. This is, to our knowledge, the first systematic review of the literature to investigate solely to elucidate the seizure spectrum by unfolding epileptogenicity of the SARS CoV-2 and potential pathways of neuroinvasion.
 Methods: A systematic literature search was performed in PubMed and Embase database following standard guidelines, using specific keywords based on epileptic seizure onset described from December 01, 2019, to July 17, 2020
 Results: A total of 17 studies were included ranging from case reports, series of cases, multicentre cross-sectional study with the first-time onset of seizure associated with an epileptic origin. We excavated causes of complex COVID-19 related neurological manifestations, e.g., cerebrovascular diseases, encephalitis, demyelinating lesions, cytokine storm and proposed routes of SARS-CoV-2 entry into the nervous system to understand the mechanism of an epileptic seizure.
 Conclusion: COVID-19 is a potent neuropathogen which causes the new onset of epileptic seizures should get diagnostic recognition to evade possible deterioration of neurological conditions. However, more shreds of evidence from the future will further elucidate the epileptogenic potential of the pandemic.

SGLT2 Inhibitors: The “Metabolic Molecule” Or “Disease Modifying Anti Metabolic Drugs- DMAMDs”?

The major health hazard of the modern world, “Metabolic Syndrome” or “Syndrome X”, defined by WHO, as pathologic condition characterised by abdominal obesity, insulin resistance, hypertension and dyslipidemia [1]. The criteria for diagnosis are listed in Figure 1 [2]. It is being accepted almost a decade ago that we are in the phase of epidemic for this Non Communicable Condition. Though it was started in western world, spread of western lifestyle across the globe, truly it has now become the major global issue. Until recently the condition was far more prevalent in urban population than rural but in today’s time, especially in Country like India, the incidence showed trends towards becoming almost equal [3]. Though recognised all over the world, the condition is rather dealt as managing different component(s) of the syndrome rather than taking the syndrome per say as diagnosis. We rather tend to care much of those patients who actually show prominently one or more components of metabolic syndrome, and this approach is leading us to neglect rather major bulk of patients who, in spite qualifying for criteria of diagnosis of metabolic syndrome, where not only patients are in early asymptomatic phase, but also the physicians caring for them do not reinforce the importance of the needed care at this very moment to prevent or delay the progression of the condition. Healthcare all over world, particularly in India has shown enormous growth, in terms of not only infrastructure but also skill development [4]. Today we do have much better level of expertise in all the subspecialty with regards to high end care of all such conditions arise from one or more components of metabolic syndrome like Heart Failure, Chronic liver disease, chronic kidney disease and Diabetes (related complication). In developing country like India, somewhere 3 to 4 decades ago to subject a patient for liver or kidney transplant used to be mere dream of treating consultants but today we are not only doing the transplants smoothly but also survival rate is getting better and better [5]. But its quiet unfortunate that in spite of all these progresses, the actual numbers of such patients needing high end care is steadily on rise, thanks to increase in life expectancy in general and relatively better exposure to needed healthcare [5]. But author do strongly believe that still whatever we are seeing is more at treatment cum cure level but nothing much at prevention level is going on. In decades to come, we have large population at risk, at this very moment, for all such advanced staged chronic metabolic conditions. We are in genuine need of a molecule which can be offered to all such early or intermediate metabolic syndrome patient, expecting the improvement in almost all the aspect on the syndrome. Author do believe, the group of drugs known as “SGLT2 Inhibitors”, an originally used for Hyperglycemia management, has now expanded its preventive effects on various metabolic conditions, showing promising results in all the trials and early real world evidences, is the real nomination for the “Metabolic Molecule” or “Disease modifying anti metabolic drugs- DMAMDs” of today.

Microplastics in spotted seal cubs (Phoca largha): Digestion after ingestion?

Microplastic pollution is a growing global concern. Early evidences have suggested that microplastics ingestion occurs in various marine organisms. However, there is very limited information regarding the fate of microplastics after ingestion by marine mammals. The present study investigated the characteristics of microplastics identified in spotted seal cubs, Phoca largha. Microplastics were identified in the stomach, small intestine and large intestine of the seal cubs. Poly(ethylene terephthalate), polypropylene and poly(acrylonitrile:acrylic acid) were the main components of the total microplastic contents isolated, with fibers being the main morphological categorization. Importantly, the average size of microplastics detected in the stomach were larger than those in the small intestine (p < 0.05) and large intestine (p > 0.05), while the average abundance in stomach was lower than in the small intestine and large intestine (p > 0.05); these findings imply that microplastics that are ingested might be fragmented into smaller particles in the stomach during digestion before reaching the intestine. These data provide a novel signal for further understanding the fate of microplastics in marine mammals.

Effectiveness of online teaching and learning of wood science and technology courses during the COVID-19 pandemic: Early evidences from a survey of Malaysian universities

Wood Science and Technology (WST) courses have been traditionally taught face-to-face in most of the universities worldwide, but the global COVID-19 pandemic has disrupted classroom lessons, replacing them with online teaching and learning methods. To assess the effectiveness of these online methods, a survey of students and academics were carried out in several Malaysian universities offering the WST programs. The survey revealed that students were mostly challenged by the problems related to access to internet, computer hardware, and lack of communication. Further, the student-centered learning method was preferred, while non-technical courses were the most suited for online teaching and learning. In contrast, academics appear to prefer pre-recorded lectures and recorded videos as the most common method for teaching online, while continuous assessment of the student’s progress found limited application. The results found that to enhance the effectiveness of teaching and learning online of WST courses, factors such as connectivity, student’s preparedness, content design, pedagogical approach, peer communication, and the teacher’s presence, must be taken into consideration and improved.

The impact of COVID-19 on the travel and leisure industry returns: Some international evidence

This research crucially investigates COVID-19 variables’ impacts on the changing distributions of travel and leisure industry returns across 65 countries via a quantile regression model that uses daily data from December 2019 to May 2020 to provide early evidences from a panel of countries. We find that the change rate in COVID-19 deaths exerts more substantial negative effects on industry returns at majority quantiles than does the impact from the number of confirmed cases. The latter number only saliently and negatively influences the lowest return quantiles, revealing a nonlinear effect of confirmed cases. The study identifies a V-shape correlation between the number of cases recovered and travel and leisure industry returns (i.e. a negative impact at the lower quantiles, but a positive impact at higher quantiles) across return quantiles. This likely denotes that confirmed cases grow exponentially and that their effect may overwhelm the impact of the number of recovered cases. Lastly, this study presents a positive correlation between government response stringency index and returns.

The role of matrix metalloproteinases in early and late gonarthrosis manifestations

The aim of this research was to study the specifics of the matrix metallopeptidase system in early and late gonarthrosis (GA) manifestations. Material and Methods — 37 patients of the main group (0-I stages of GA), 30 patients of the comparison group (III-IV stages of GA) and 30 healthy individuals of the control group underwent sonography and T2-relaxometry of their knee joints. The 24-h excretion of urinary C-telopeptide fragments of type II collagen (СTX-II) as well as serum concentrations of matrix metalloproteinases-3 and -8 (MMP-3, MMP-8), and tissue inhibitor of metalloproteinases (TIMP-1) were also registered. Results — We detected increases in urinary СTX-II to 3.9 [2.5; 4.5] mg/d, MMP-8 to 364.7 [215; 434] pg/ml and TIMP-1 to 806 [559; 1157] pg/ml in the main group; to 9.7 [6.8; 10.2] mg/d, 579 [463; 663] pg/ml and 1256 [1029; 1330] pg/ml in the comparison group. The presence (p=0.04) of strong positive correlation (R=0.7) between the 24-h urinary СTX-II excretion and the change of MRI-signal characteristics for the areas of hyaline cartilage under the heaviest load on knee joints T2 relaxometry evidence was observed as well as the presence (p=0.001) of strong positive correlation (R=0.7) between MMP-8 and 24-h urinary СTX-II extraction. In early GA stages a strong positive correlation (R=0.6) was observed between MMP-8 and TIMP-1 (p=0.04) as well as 24-h urinary СTX-II excretion and TIMP-1 (R=0.5) at p˂0.001). Conclusion — Type II collagen degradation with MMP-8/TIMP-1 imbalance is one of the relevant mechanisms of the hyaline articular cartilage extracellular matrix disorganization in early and late GA evidences. The rearrangement of correlations between MMP-8 and TIMP-1 indicates the change in interaction mechanisms for GA proteolytic enzyme system components.

How are small and medium enterprises in Malaysia’s furniture industry coping with COVID-19 pandemic? Early evidences from a survey and recommendations for policymakers

In the wake of the global COVID-19 pandemic and the subsequent movement control order (MCO) in Malaysia, an on-line survey was undertaken involving 748 small and medium enterprises (SMEs) in the furniture industry. The main objective was to examine the impact of the pandemic and the subsequent MCO on the various business aspects of the SMEs as well as to make recommendations to the government on supportive measures for the SMEs. The survey found that although all aspects of the business were impacted, the two major concerns of the SMEs during this crisis were the financial management and the supply chain disruptions. Inevitably, it was found that most of the SMEs were operating well below capacity, which was a huge financial strain on their business viability. It was recommended that the government provide measures to help the SMEs manage their cash-flow and ease the restrictions to facilitate supply-chain commencement that is crucial to their business. The survey also revealed that most SMEs acknowledged the importance of automation and the adoption of technologies. Respondents regarded the shift towards Industry 4.0 was inevitable as a means increase their resilience when facing future uncertainties.

Comprehensive profiling of MDM2/TP53 genomic aberration in Chinese patients with diverse malignancies.

e13508 Background: Murine double minute-2 (MDM2) has increasing clinic relevance as preclinical and early clinical evidences have showed that the MDM2 inhibitors are promising alternative treatments for patients with MDM2-amplified (-amp) and TP53-wild-type (-WT) tumors by preventing TP53 protein degradation. However, exploration into genomic landscape of MDM2/TP53 across various solid tumors in Chinese patients is still limited. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor samples were collected from 10010 Chinese patients with solid tumors and subjected to a clinical-grade next-generation sequencing (NGS)-based 450 gene panel testing carried out by a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Genomic alterations (GAs) including single base substitutions, short and long insertion/deletions (Indels), copy number variations, gene fusions, and rearrangements were analyzed. Tumor mutational burden (TMB) was measured by a NGS algorithm. Results: Amplification of MDM2 occurred in 3.3% of Chinese patients. MDM2-amp was detected most frequently in soft tissue sarcoma (STS, 11.4 %), melanoma (10.3 %) and osteosarcoma (6.3 %). Notably, MDM2-amp was revealed to be mutually exclusive with TP53-mut in most tumor types other than esophageal carcinoma (93.9 %), head and neck carcinoma (68.4%) and ovarian carcinoma (50 %). Tumors with highest frequencies of MDM2-amp/ TP53-WT were melanoma (100%), osteosarcoma (100%) and urothelial carcinoma (100 %). The most common co-altered genes accompanied with MDM2-amp were FRS2 (84%), CDK4 (38%), EGFR (26%), TP53 (17%) and GLI1 (14%). 82.8% patients who had one or more co-alterations potentially targetable with either FDA-approved or investigational agent. Moreover, TMB of MDM2-amp tumors were significantly lower than that of MDM2-WT and MDM2-mutation (-mut) tumors (median TMB: 3.1 vs. 4.6 vs. 10.8, p &lt; 0.001 respectively). Conclusions: MDM2 amplification was found in 3.3% of 10010 Chinese cancer patients, 83.4% of whom harbored wild-type TP53 that were potentially responsive to MDM2 inhibitors. In addition, 82.8% of the patients with MDM2-amp harbored genomic co-alterations and were potentially therapy targetable. This study provided insights into identifying patients who might potentially benefit from anti-MDM2 therapies.

Stereotactic Ablative radiation therapy (SABR) for cardiac arrhythmia: A new therapeutic option?

Stereotactic ablative radiation therapy (SABR) is used in non-oncologic indications, recently even for cardiac arrhythmias. Thus, aim of this analysis is to review preclinical, early clinical evidences and future direction of the latter new treatment approach. A collection of available data regarding SABR and cardiac arrhythmias was made, by Pubmed research and 2 independent researchers, including preclinical and clinical data. A review of ongoing trials was conducted on ClinicalTrials.gov. Preclinical research conducted in animal models showed that a safe and effective noninvasive treatment approach for cardiac arrhythmias could be represented by SABR with a median time of response around 2-3months. The treatment dose plays a crucial role: the atrioventricular node would seem more radiosensitive than the other cardiac electric zones. Clinical data, such as published case series, case reports and early prospective studies, have already suggested the feasibility, efficacy and safety of SABR (25Gy in one session) for refractory ventricular arrhythmias. Considering the ongoing trials of SABR and new technological improvements in radiotherapy (e.g. hybrid magnetic resonance) and in arrhythmias noninvasive mapping systems, the future analyses will improve the reliability of those preliminary results.

Early evidences of niche shifts in estuarine fishes following one of the world's largest mining dam disasters

The Fundão dam collapse occurred on November 2015 in Mariana city (Brazil), provoking a series of ecological impacts over the Doce river basin and its nearshore environment. However many impacts over fishery target fauna (fish and shrimp) are still unknown or underestimated due to the lack of baseline data in the region. In the present study we assessed the isotopic niches modeled from δ13C and δ15N signatures of six estuarine fish species before and after the impact to assign potential shifts at the population- and community-level. We showed isotopic niche has altered in all studied species irrespective of its trophic group and habitat use. Niche community metrics indicated a depletion of trophic diversity and basal resources of the whole community after the impact. Food web changes as we reported here can impair the energy transfer through the food chain and put at risk the sustainability of small fisheries that rely upon local resources.

Biochemical predictors of cartilaginous tissue metabolic disorders for early osteoarthrosis evidence diagnostics.

The complete laboratory and clinical instrumental examination was conducted, it included serum COMP test, circadian excretion of type II collagen C-terminal telopeptides Urine CartiLaps (СТХ II) and Т2 relaxometry in 29 patients of both sexes of the main group with early (0-I) X-ray osteoarthrosis stages, 30 subjects of comparison group with no X-ray osteoarthrosis evidences aged 44.7±5.9 years and 25 healthy subjects aged 26.3±2.6 years of the control group. The increase (р<0,05) of COMP and Urine CartiLaps levels as well as the increase of Т2 relaxation signal was found at early osteoarthrosis evidences. It was proven that there was (р<0.01) a connection (R=0.8) between COMP and Urine CTX II levels as well as (р<0.05) results of Т2 relaxometry (R=0.8). It was proven that collagen anisotropy and formation of chondromalacia areas as Т2 relaxometry showed in patients with early OA evidences were connected with accumulation of serum COMP and increase of type II collagen circadian renal excretion. The combination of laboratory and radiological methods of articular hyaline cartilage assessment may be used for finding early osteoarthrosis stages.

Is seaweed extract an elicitor compound? Changing proline content in drought-stressed bean plants

Abiotic stresses negatively affect crop development and yield. However, the use of seaweed extracts can alleviate production losses through improvement of the antioxidant system and synthesis of compatible osmolytes. The aim of this study was to assess the effects of Ascophyllum nodosum extract on antioxidant response and yield of common bean plants (Phaseolus vulgaris) under drought stress. Therefore, two methods of application (foliar spray and soil irrigation) and two doses (5 and 10 mL L-1) were tested, whereas untreated plants were used as control. There were no significant differences in malondialdehyde and hydrogen peroxide contents among treatments, indicating that application of seaweed extract did not change the oxidative status in treated plants when compared to the control ones. On the other hand, the use of seaweed extract increased proline content even prior to drought stress (46.3 to 145.4% when compared to the control), and this increment remained until the 10th day of stress (from 60.1 to 201.7% over the reference plants), supporting early evidences that A. nodosum extract is a plant elicitor. The yield parameters were not affected by the extract, probably due to the severe drought stress which plants were submitted. The results suggest that A. nodosum extract affects proline metabolism in Phaseolus vulgaris plants, making the synthesis of this osmolyte more responsive to drought stress because seaweed-treated plants presented a higher proline content than the control ones during the exposure to water deficit.

Skeletal Muscle Insulin Resistance as a Precursor to Diabetes: Beyond Glucoregulation.

Prevalence of Type 2 Diabetes Mellitus (T2DM) has reached pandemic levels in the Western societies. T2DM begins with the development of peripheral insulin resistance which prior research suggests may commonly originate within the skeletal muscle. A number of mechanisms have been proposed for the development of muscle insulin resistance including those of classical glucose handling, and also other cellular derangements observed in this disease which include mitochondrial degeneration, alterations in muscle protein turnover and early evidences for dysregulation of the microRNAs. The purpose of the current review is to examine the current findings on these latter aspects of mitochondrial maintenance, protein turnover and microRNA dysregulation along with the potential implications for these derangements in the development of insulin resistance and hence T2DM. We summarize multiple evidences for the degeneration of mitochondria and known elements of the processes regulating mitochondrial quality. Subsequently, we examine current findings of the alterations in muscle protein synthesis and autophagic protein degradation in T2DM and potential feedback of these systems onto canonical insulin signaling. Finally, evidences have emerged for the dysregulation of microRNAs in muscle insulin resistance. Of note early data point to several microRNAs altered by the insulin resistant state which exhibit relations to classic insulin signaling and the other processes discussed here. Considering that T2DM may be initiated with muscle insulin resistance, improved understanding of the dysregulation of these metabolic parameters of skeletal muscle in the pathogenesis of T2DM may be key to developing efficacious therapeutic modalities to prevent and treat this condition.

Abstract A179: The BRD4 degrader MZ1 exhibits potent antitumoral activity in diffuse large B cell lymphoma of the activated B cell-like type

Abstract Background: Bromodomain and Extra-Terminal domain (BET) proteins are epigenetic readers that play a fundamental role in transcription regulation. Preclinical and early clinical evidences sustain BET targeting as a promising novel approach for cancer treatment. BET degraders are chimeric compounds merging a BET inhibitor, which allows the binding to BET bromodomains, linked to an additional small molecule, which mediates the binding to an E3 ubiquitin ligase complex, triggering BET proteins degradation via the proteasome. These compounds are based on the concept of the PROTAC (Proteolysis targeting Chimera) (Sakamoto et al, PNAS 2001). MZ1 is a potent BRD4 degrader that exploits JQ1 for BET bromodomain binding and the von Hippel Lindau-containing complex for protein degradation (Zengerle et al, ACS Chem Biol 2015; Gadd et al., Nat Chem Biol 2017). MZ1 showed potent antiproliferative activity in AML cell lines (Chan et al. J Med Chem 2017). Here, we present data on the antitumor activity of MZ1 in diffuse large B cell lymphoma of the activated B cell like (ABC DLBCL). Materials and Methods: Established lymphoma cell lines were exposed for 72 hours to increasing doses of the compounds. Cell proliferation was evaluated by using MTT assay. FACS analysis was performed to measure apoptotic activation (Annexin V, threshold of 1.5 fold) after 72 hours of treatment. Results: The antitumor activity of the BET degrader MZ1, of its negative control epimer cisMZ1 and, as comparison, of the BET inhibitor OTX015/MK-8628 was assessed in seven cell lines derived from diffuse large B cell lymphoma of the activated B cell like (ABC DLBCL). MZ1 was very active with a median IC50 of 50nM (range, 5-150 nM). No activity was seen with cisMZ1. BET degrader was more active in vitro than the BET inhibitor, which presented a median IC50 of 125 nM (range, 80-400 nM) (P=0.024). Importantly, MZ1 (500nM, 72 h) induced apoptosis in all the seven ABC DLBCL cell lines, while, in accordance with previous data (Boi et al, Clin Cancer Res 2015), OTX015 (500nM, 72 h) was cytotoxic only in 2/7 cell lines (P=0.021). No apoptosis was observed with cisMZ1 (500nM, 72 h). Conclusion: The BRD4 degrader MZ1 had a strong cytotoxic activity in all the ABC-DLBCL cell lines we tested, and, at least in vitro, it elicited more profound effects than BET inhibitors, and encourages further investigations. Citation Format: Chiara Tarantelli, Hillarie Ekeh, Carmelo Moscatello, Eugenio Gaudio, Andrea Testa, Emanuele Zucca, Anastasios Stathis, Alessio Ciulli, Francesco Bertoni. The BRD4 degrader MZ1 exhibits potent antitumoral activity in diffuse large B cell lymphoma of the activated B cell-like type [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A179.

Infiltrating mast cells enhance benign prostatic hyperplasia through IL-6/STAT3/Cyclin D1 signals.

Early evidences have showed that mast cells could infiltrate into benign prostatic hyperplasia (BPH) tissues, but the exact role of mast cells in BPH development remains unclear. In this study, we identified more mast cells existing in human BPH tissues compared with that in the normal prostate. In the in vitro co-culture system, BPH-1 prostate cells promoted activation and migration of mast cells, and mast cells conversely stimulated BPH-1 cells proliferation significantly. Molecular analysis demonstrated that mast cell-derived interleukin 6 (IL-6) could activate STAT3/Cyclin D1 signals in BPH-1 cells. Blocking IL-6 or STAT3 partially reverse the capacity of mast cells to enhance BPH-1 cell proliferation. Our findings suggest that infiltrating mast cells in BPH tissues could promote BPH development via IL-6/STAT3/Cyclin D1 signals. Therefore, targeting infiltrating mast cells may improve the therapeutic effect of BPH.