Histone deacetylases as new therapy targets for platinum-resistant epithelial ovarian cancer

Introduction: In developed countries, ovarian cancer is the fourth most common cancer in women. Due to the nonspecific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets. Methods: We have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription. Results and conclusion: Analysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies

Conjunctival-corneal melt in association with carotid artery stenosis

Rosalind MK Stewart1, Say Aun Quah1, Dan Q Nguyen2, Stephen B Kaye11Royal Liverpool University Hospital, Liverpool, UK; 2Bristol Eye Hospital, Bristol, UKPurpose: To report a case of severe conjunctival-corneal melt in association with carotid artery stenosis.Methods: Observational case report.Results: A 76-year-old man with a history of bilateral severe carotid artery occlusion and nonarteritic ischemic optic neuropathy developed a spontaneous bulbar conjunctival defect. Despite intensive lubrication, and attempts at surgical closure including an amniotic membrane patch graft, it progressed with subsequent adjacent corneal perforation. Thorough investigations revealed no underlying disease, except markedly delayed episcleral vessel filling on anterior segment fluorescein angiography.Conclusions: Neovascularisation is a known factor in the inhibition of ulceration. In light of the findings in this report, ocular ischemia should be considered as a cause or contributing factor in the differential diagnosis of conjunctival-corneal melt.Keywords: conjunctival melt, corneal melt, ocular ischemia, carotid artery stenosi

Overexpression of RPA194 is associated with mutant p53 in advanced human liver cancer

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and in the United States alone, an estimated 42,000 adults were diagnosed with primary liver cancer in the year of 2022. Sorafenib is the first systemic therapy approved for patients with advanced-stage HCC, after a landmark study revealed an improvement in median overall survival from 8 to 11 months. New drugs — lenvatinib in the frontline and regorafenib, cabozantinib, and ramucirumab in the second line — have also been demonstrated to improve clinical outcomes, although the median overall survival remains ~1 year. Therefore, discovery of new potential molecular targets is required which can be used in rationale designing of prevention and treatment strategies against advanced liver cancer. Ribosome biogenesis process is dysregulated in most of the cancer cells because of high demand of protein synthesis. However, the role of ribosome biogenesis components were least studies in cancer setting. Here, we found that POLR1A (RPA194) a catalytic subunit of RNA polymerase I is significantly (

Honey: A Natural Recipe for the Management of Pancreatic Cancer

Background: Pancreatic cancer (PanCa) is the fourth deadliest cancer worldwide and expected to become the second deadliest cancer by 2030. In the USA, the National Cancer Institute put forth a grim prediction stating that there will be 64,050 new cases in 2023 alone and about 50,000 of these patients will die. The first line treatment for pancreatic cancer is Folfrinox, a three-drug regimen consisting of 5-Fluorouracil, irinotecan, and oxaliplatin. The second line treatment is gemcitabine combined with paclitaxel. Only 19% of patients who are prescribed the former regimen survive past 18 months of treatment while just 6% of patients survive past 18 months with gemcitabine. In addition to these regimens, the overall five-year survival rate for pancreatic cancer patients only stands at 11%. Therefore, the discovery of potentially new molecular targets is warranted. In pancreatic cancer, the ribosome biogenesis is dysregulated because the tumor cells require an increased amount of protein synthesis. Furthermore, RPA194, a catalytic subunit of RNA Polymerase I, is overexpressed to meet this demand by elevating the number of ribosomes. Apoptotic pathways are also downregulated to enhance the survivability of PanCa. Methods: The cytotoxicity of honey was determined in four PanCa cell lines i.e., AsPc-1, MiaPaCa-2, Capan-2, and HPAF-2, using MTT assay. Western blotting was done to assess the regulatory role of honey on distinct proteins involved in ribosome biogenesis, nuclear stress, and apoptosis. Polymerase Chain Reaction (PCR) was utilized to determine the expression of genes within these cancer cells. Confocal microscopy was used to detect proteins associated with ribosome biogenesis and nuclear stress. Cell cycle analysis was performed to assess cellular arrest in specific stage of the cell cycle. The percentage of cells that underwent programmed cellular death was measured by apoptosis assay. Results: MTT analysis indicated that honey exerted dose-dependent cellular cytotoxicity in AsPc- 1, MiaPaCa-2, Capan-2, and HPAF-2 cells, four pancreatic cancer cell lines. The western blotting analysis revealed that the treatment with honey markedly targeted the process of ribosome biogenesis via downregulating the expression of RPA-194 (catalytic unit of RNA Pol), RPA-135, RPL-29, c-Myc, nucleolin (NCL), and fibrillarin (FBL) in AsPC-1 and MiaPaCa-2 cells. The mRNA expression analysis also indicated the effect of honey on ribosome biogenesis in PanCa cells. The same findings were further validated through confocal microscopy. Cell cycle analysis indicated a concentration-dependent decrease of cancer cells in the G1 stage and a concentration-dependent G2/M phase arrest in AsPc-1 and MiaPaCa-2 cells. Apoptosis assay indicated early and late-stage apoptosis in cancer cells with honey administration. Furthermore,honey also induced the apoptosis in AsPC-1 and MiaPaCa-2 cells via targeting p53 (truncated and mutated, respectively), Bcl-2 (important for apoptosis), cleaved PARP, and Caspase-3 expression. Conclusions: Honey, as a natural compound, can serve as an anticancer agent via targeting both ribosome biogenesis and apoptotic pathways. Honey has the potential to become a therapeutic of interest for future patients due to its medicinal effects, natural properties, and attractive prices. However, more studies are warranted to understand the complex and diverse mechanisms that honey utilizes in combating pancreatic cancer

Epidemiology, practice of ventilation and outcome for patients at increased risk of postoperative pulmonary complications

BACKGROUND Limited information exists about the epidemiology and outcome of surgical patients at increased risk of postoperative pulmonary complications (PPCs), and how intraoperative ventilation was managed in these patients. OBJECTIVES To determine the incidence of surgical patients at increased risk of PPCs, and to compare the intraoperative ventilation management and postoperative outcomes with patients at low risk of PPCs. DESIGN This was a prospective international 1-week observational study using the ‘Assess Respiratory Risk in Surgical Patients in Catalonia risk score’ (ARISCAT score) for PPC for risk stratification. PATIENTS AND SETTING Adult patients requiring intraoperative ventilation during general anaesthesia for surgery in 146 hospitals across 29 countries. MAIN OUTCOME MEASURES The primary outcome was the incidence of patients at increased risk of PPCs based on the ARISCAT score. Secondary outcomes included intraoperative ventilatory management and clinical outcomes. RESULTS A total of 9864 patients fulfilled the inclusion criteria. The incidence of patients at increased risk was 28.4%. The most frequently chosen tidal volume (VT) size was 500 ml, or 7 to 9 ml kg1 predicted body weight, slightly lower in patients at increased risk of PPCs. Levels of positive end-expiratory pressure (PEEP) were slightly higher in patients at increased risk of PPCs, with 14.3% receiving more than 5 cmH2O PEEP compared with 7.6% in patients at low risk of PPCs (P < 0.001). Patients with a predicted preoperative increased risk of PPCs developed PPCs more frequently: 19 versus 7%, relative risk (RR) 3.16 (95% confidence interval 2.76 to 3.61), P < 0.001) and had longer hospital stays. The only ventilatory factor associated with the occurrence of PPCs was the peak pressure. CONCLUSION The incidence of patients with a predicted increased risk of PPCs is high. A large proportion of patients receive high VT and low PEEP levels. PPCs occur frequently in patients at increased risk, with worse clinical outcome

Honey Targets Ribosome Biogenesis Components to Suppress the Growth of Human Pancreatic Cancer Cells

Simple Summary Pancreatic cancer (PanCa) is one of the deadliest forms of cancer with limited therapeutic options. The available conventional therapies are highly toxic and often show resistance. Accumulating evidence suggests that dysregulated ribosome biogenesis has been linked to the survival and aggressive phenotypes of many tumor types, including PanCa. Thus, targeting ribosome biogenesis could be a novel approach for suppressing the growth of PanCa. The current study aimed to investigate the anti-cancer efficacy and underlying molecular mechanisms of honey against PanCa. Our results demonstrated that honey induces apoptosis and inhibits the growth and invasive potential of PanCa cells by targeting ribosome biogenesis components and c-Myc expression. This study suggests that honey can be used as an adjuvant along with conventional chemo/radiation therapy or immunotherapy for the management of PanCa. Abstract Pancreatic cancer (PanCa) is one of the deadliest cancers, with limited therapeutic response. Various molecular oncogenic events, including dysregulation of ribosome biogenesis, are linked to the induction, progression, and metastasis of PanCa. Thus, the discovery of new therapies suppressing these oncogenic events and ribosome biogenesis could be a novel therapeutic approach for the prevention and treatment of PanCa. The current study was designed to investigate the anti-cancer effect of honey against PanCa. Our results indicated that honey markedly inhibited the growth and invasive characteristics of pancreatic cancer cells by suppressing the mRNA expression and protein levels of key components of ribosome biogenesis, including RNA Pol-I subunits (RPA194 and RPA135) along with its transcriptional regulators, i.e., UBTF and c-Myc. Honey also induced nucleolar stress in PanCa cells by reducing the expression of various nucleolar proteins (NCL, FBL, and NPM). Honey-mediated regulation on ribosome biogenesis components and nucleolar organization-associated proteins significantly arrested the cell cycle in the G2M phase and induced apoptosis in PanCa cells. These results, for the first time, demonstrated that honey, being a natural remedy, has the potential to induce apoptosis and inhibit the growth and metastatic phenotypes of PanCa by targeting ribosome biogenesis

Clinical significance of targeting ribosome biogenesis in pancreatic cancer therapy

Pancreatic cancer (PanCa) is the third leading cause of cancer-related deaths in the United States with limited therapeutic options available. Gemcitabine (GEM), a deoxycytidine nucleoside analog is currently considered the most effective therapy for PanCa. However, it shows only a marginal survival benefit of six months. Aberrant ribosome biogenesis occurs in most tumor types. We observed that PanCa cells are addicted to ribosome biogenesis (RiBi), which supports their highly aggressive metastatic phenotypes. Thus, strategically targeting RiBi process could be one of the ideal strategies for the prevention and treatment of PanCa. In this study, we elucidated the molecular mechanisms of POLR1A (RPA194) overexpression and how its targeting along with p53 status impacts RNA polymerase I inhibitor therapy against PanCa. The expression level of RPA194 was significantly elevated in pancreatic tumor tissues when compared with adjacent normal pancreatic tissues. BMH-21 is a potent pharmacological inhibitor of RNA Pol I, which is known to degrade RPA194 protein. Our results demonstrated that BMH-21 can selectively induce apoptosis in various PanCa cells but not in HPNE cells. We also found that the cytotoxic effect of BMH-21 was dependent on the expression pattern of RPA-194 and p53 status. We further examined the therapeutic efficacy of BMH-21 in orthotopic xenograft mouse models by using two different PanCa cells, AsPC1 which contains non-functional p53 and MIA PaCa-2 which contains functional mutant p53. We observed that BMH-21 significantly inhibited the growth of tumors derived from both cancer cell lines. Interestingly, BMH-21-mediated inhibition of tumor growth was more significant in tumors derived from MIA PaCa-2 cells compared to AsPC1 cells. Further examination revealed that the inhibition of tumor growth was correlated with RPA194 degradation followed by inhibition of cell proliferation. Overall, our results strongly suggest that BMH-21 is a promising non-toxic agent for the treatment of advanced PanCa and its therapeutic potential depends on RPA194 expression and p53 status in PanCa cells

Influência de diferentes agentes auxiliares do preparo biomecânico na obturação de canais laterais artificiais

The purpose of the present study was to evaluate the influence of some auxiliary agents of biomechanical preparation of the root canal on the filling of artificial lateral canals in extracted human teeth. A total of eighty single-rooted teeth were employed, which were submitted to preparation of three artificial lateral canals in one of the proximal aspects at the cervical, middle and apical thirds, besides one in the buccal aspect. The main canals were prepared by Profile 0.4 rotary instruments through the crown-down technique and irrigated with the irrigants investigated, as follows: Group A - 1% sodium hypochlorite and final irrigation with trisodium EDTA for 5 minutes; Group B - Endogel (2% chlorhexidine gel); Group C - Endo PTC and Dakin's solution and final irrigation with Tergentol- Furacin; and Group D - File Eze. The root canals were obturated by the Tagger's hybrid technique and then radiographed for assessment of the penetration rate of the filling materials in the lateral canals. Analysis of the results demonstrated no statistically significant difference (pObjetivou-se avaliar a influência de alguns agentes auxiliares do preparo biomecânico do canal radicular, na obturação de canais laterais artificiais em dentes humanos extraídos. Foram utilizados oitenta dentes unirradiculados nos quais, previamente, foram confeccionados três canais laterais artificiais em uma das paredes proximais, nos terços cervical, médio e apical e um canal na parede vestibular. Os canais principais foram preparados com instrumentação rotatória, instrumentos Profile 0.4, pela técnica rotatória coroa- ápice e irrigados com a substância irrigadora estudada, sendo no grupo A - hipoclorito de sódio a 1% e irrigação final com EDTA trissódico por 5 minutos; grupo B - Endogel (gel de clorexidina a 2%); grupo C - Endo PTC e solução de Dakin e irrigação final com tergentol-furacin segundo a técnica de Paiva e Antoniazzi e no grupo D - File Eze. Os canais foram obturados pela técnica híbrida de Tagger e, então, radiografados para a análise das extensões de penetração dos materiais obturadores nos canais laterais. Após a análise dos resultados, conclui-se que não houve diferença estatística significante (

Validation of the TROPOspheric Monitoring Instrument (TROPOMI) surface UV radiation product

The TROPOspheric Monitoring Instrument (TROPOMI) onboard the Sentinel-5 Precursor (S5P) satellite was launched on 13 October 2017 to provide the atmospheric composition for atmosphere and climate research. The S5P is a Sun-synchronous polar-orbiting satellite providing global daily coverage. The TROPOMI swath is 2600 km wide, and the ground resolution for most data products is 7:23:5 km2 (5:63:5 km2 since 6 August 2019) at nadir. The Finnish Meteorological Institute (FMI) is responsible for the development of the TROPOMI UV algorithm and the processing of the TROPOMI surface ultraviolet (UV) radiation product which includes 36 UV parameters in total. Ground-based data from 25 sites located in arctic, subarctic, temperate, equatorial and Antarctic areas were used for validation of the TROPOMI overpass irradiance at 305, 310, 324 and 380 nm, overpass erythemally weighted dose rate/UV index, and erythemally weighted daily dose for the period from 1 January 2018 to 31 August 2019. The validation results showed that for most sites 60 % 80% of TROPOMI data was within 20% of ground-based data for snow-free surface conditions. The median relative differences to ground-based measurements of TROPOMI snow-free surface daily doses were within 10% and 5% at two-Thirds and at half of the sites, respectively. At several sites more than 90% of cloud-free TROPOMI data was within 20% of groundbased measurements. Generally median relative differences between TROPOMI data and ground-based measurements were a little biased towards negative values (i.e. satellite data ground-based measurement), but at high latitudes where non-homogeneous topography and albedo or snow conditions occurred, the negative bias was exceptionally high: from 30% to 65 %. Positive biases of 10 % 15% were also found for mountainous sites due to challenging topography. The TROPOMI surface UV radiation product includes quality flags to detect increased uncertainties in the data due to heterogeneous surface albedo and rough terrain, which can be used to filter the data retrieved under challenging conditions