Biallelic EPCAM deletions induce tissue-specific DNA repair deficiency and cancer predisposition.

We report a case of Mismatch Repair Deficiency (MMRD) caused by germline homozygous EPCAM deletion leading to tissue-specific loss of MSH2. Through the use of patient-derived cells and organoid technologies, we performed stepwise in vitro differentiation of colonic and brain organoids from reprogrammed EPCAMdel iPSC derived from patient fibroblasts. Differentiation of iPSC to epithelial-colonic organoids exhibited continuous increased EPCAM expression and hypermethylation of the MSH2 promoter. This was associated with loss of MSH2 expression, increased mutational burden, MMRD signatures and MS-indel accumulation, the hallmarks of MMRD. In contrast, maturation into brain organoids and examination of blood and fibroblasts failed to show similar processes, preserving MMR proficiency. The combined use of iPSC, organoid technologies and functional genomics analyses highlights the potential of cutting-edge cellular and molecular analysis techniques to define processes controlling tumorigenesis and uncovers a new paradigm of tissue-specific MMRD, which affects the clinical management of these patients.

An allomaltol derivative triggers distinct death pathways in luminal a and triple-negative breast cancer subtypes.

Breast cancer is the most common cancer in women that shows a predisposition to metastasize to the distant organs. Kojic acid is a natural fungal metabolite exhibiting various biological activities. Compounds derived from kojic acid have been extensively studied and proved to demonstrate anti-neoplastic features on different cancer types. In the present study, allomaltol-structural analog of kojic acid and its seven derivatives including four novel compounds, have been synthesized, characterized and their possible impact on breast cancer cell viability was investigated. It was discovered that compound 5, bearing 3,4-dichlorobenzyl piperazine moiety, could decrease the viability of both MCF-7 and MDA-MB-231 cell lines distinctively. To ascertain the death mechanism, cells were subjected to different tests following the application of IC50 concentration of compound 5. Data obtained from lactate dehydrogenase activity and gene expression assays pointed out that necrosis had taken place predominantly in MDA-MB-231. On the other hand, in MCF-7 cells, the p53 apoptotic pathway was activated by overexpression of the pro-apoptotic TP53 and Bax genes and suppression of the anti-apoptotic Mdm-2 and Bcl-2 genes. Furthermore, Bax/Blc-2 ratio was escalated by 3.5 fold in the study group compared to the control. Compound 5 did not provoke drug resistance in MCF-7 cells since the Mdr-1 gene expression, drug efflux, and H2O2 content remained unaltered. As for MDA-MB-231 cells, only a 1.4 fold increase in the Mdr-1 gene expression was detected. These results indicate the advantage of the allomaltol derivative over the chemotherapeutic agents conventionally used for breast cancer treatment that can be highly toxic and mostly lead to drug resistance. Thus, this specific allomaltol derivative offers an alternative therapeutic approach for breast cancer which needs further investigation.

A case of Inappropriate Antidiuretic Hormone Secretion Syndrome Associated with COVID-19 Pneumonia.

At the end of 2019, a novel coronavirus was identified as the cause of a cluster of pneumonia in China and it spread quickly to other countries. Although Covid-19 causes severe pneumonia, it is known that it can be associated with different diseases and prognosis of disease can be due to many of disorders such as hyponatremia. A 65-year-old female patient with sarcoidosis, cronic obstructive lung disease, hypertension and congestive heart failure presented to the emergency department with shortness of breath and fever. Oropharyngeal swab for Covid-19 PCR test was positive. After the initiation of treatment, the patient developed hyponatremia. This case is remarkable because there is no reported case of Covid-19 and inappropriate ADH syndrome coexistence and it demonstrates that there may be a correlation between Covid-19 infection prognosis and hyponatremia.

Impacts of climate change on snow accumulation and melting processes over mountainous regions in Northern California during the 21st century.

A point-location-based analysis of future climate change impacts on snow accumulation and melting processes was conducted over three study watersheds in Northern California during a 90-year future period by means of snow regime projections. The snow regime projections were obtained by means of a physically-based snow model with dynamically downscaled future climate projections. Then, atmospheric and snow-related variables, and their interrelations during the 21st century were investigated to reveal future climate change impacts on snow accumulation and melting processes. The analysis shows large reductions in snow water equivalent (SWE), snowfall to precipitation (S/P) ratio, and snowmelt through the 21st century. Timing of the peak of the SWE and snowmelt will also change in the future. Meanwhile, the analysis in this study shows that air temperature rise will affect, but will not dominate the future change in snowmelt over the study watersheds. This result implies the importance of considering atmospheric variables other than air temperature, such as precipitation, shortwave radiation, relative humidity, and wind speed even if these variables will not clearly change during the 21st century.

Reconstruction and evaluation of changes in hydrologic conditions over a transboundary region by a regional climate model coupled with a physically-based hydrology model: Application to Thao river watershed.

The differences among countries in terms of physical features, governmental policies, priorities in short- and long-term water resources management may lead to conflicts in managing and sharing of water resources over the transboundary regions. Due to no formal data sharing agreement between countries, there has been usually no data availability at transboundary regions. In this study, a methodology, in which a physically-based hydrology model was coupled with a regional climate model, is proposed to reconstruct and evaluate hydrologic conditions over transboundary regions. For the case study, Thao river watershed (TRW), within Vietnam and China, was selected. The Watershed Environmental Hydrology (WEHY) model was implemented based on topography, soil, and land use/cover information which was retrieved from global satellite data resources. The watershed model-WEHY was first validated over the TRW, and then was used to reconstruct historical hydrologic conditions during 1950-2007. The results of this study suggest no significant trend in the annual streamflow over the target watershed. In addition, there is a time shift in the wet season between the upstream sector in China and the downstream sector in Vietnam over the TRW. The annual flow contribution from the upstream sector in China to the outlet of TRW is estimated to be around 66%, and the remaining 34% contribution comes from the downstream sector in Vietnam territory. Last but not the least, the annual flow as a function of return period varies not only with the return period but also as a function of the time window, reflecting the effect of the changing regime on the streamflows at the TRW. The evolution of the flow frequency through time is an evidence of the ongoing non-stationarity in the hydrologic conditions over TRW.

HGF-1 proliferation on titanium dental implants treated with laser melting technology.

BACKGROUND: Titanium and its alloys are currently the most common dental implant materials. For the best bone-implant contact, machined titanium is subjected to various surface treatments. In the present study, proliferation of human gingivial fibroblast (HGF-1) cells on Grade 5 titanium disks covered with Grade 23 titanium by selective laser melting technology was evaluated. AIM: The main aim was to provide a novel surface procedure providing more biocompatible external structure with a biomechanically intact inner structure and increasing cell proliferation. MATERIALS AND METHODS: Forty-eight titanium Grade 5 machined disks with 5 mm of diameter was divided into four groups. Group 1, also known as the control group, was not subjected to any surface treatment. Group 2 was treated with sand-blasted, large-grid, acid-etching (SLA) technique and Group 3 was treated with selective laser melting (SLM) method. Group 4 was treated with both SLM and SLA. The surface topography was analyzed using scanning electron microscope and the roughness of the samples was evaluated via optic profilometer. Additionally, optical tensiometer was used to measure the surface wettability. To obtain further insights on biocompability of the samples, HGF-1 cell viability at 48 h was assessed with MTT assay. These results were also confirmed by fluorescent staining. Results: Although Ra value and wettability of Group 4 were the highest amongst the samples handled, based on 48 h MTT results and fluorescent staining, highest cell proliferation was observed in Group 3. CONCLUSIONS: It was verifed that the surface topography, roughness, and wettability are all crucial factors on healthy cell populations. Therefore, it was concluded that disks treated with SLM were shown to express the most suitable condition for biocompability.

Analysis of future climate change impacts on snow distribution over mountainous watersheds in Northern California by means of a physically-based snow distribution model.

The impacts of climate change on snow distribution through the 21st century were investigated over three mountainous watersheds in Northern California by means of a physically-based snow distribution model. The future climate conditions during a 90-year future period from water year 2010 to 2100 were obtained from 13 future climate projection realizations from two GCMs (ECHAM5 and CCSM3) based on four SRES scenarios (A1B, A1FI, A2, and B1). The 13 future climate projection realizations were dynamically downscaled at 9 km resolution by a regional climate model. Using the downscaled variables based on the 13 future climate projection realizations, snow distribution over the Feather, Yuba, and American River watersheds (FRW, YRW, and ARW) was projected by means of the physically-based snow model. FRW and YRW watersheds cover the main source areas of the California State Water Project (SWP), and ARW is one of the key watersheds in the California Central Valley Project (CVP). SWP and CVP are of great importance as they provide and regulate much of the California's water for drinking, irrigation, flood control, environmental, and hydro-power generation purposes. Ensemble average snow distribution over the study watersheds was calculated over the 13 realizations and for each scenario, revealing differences among the scenarios. While the snow reduction through the 21st century was similar between A1B and A2, the snow reduction was milder for B1, and more severe for A1FI. A significant downward trend was detected in the snowpack over nearly the entire watershed areas for all the ensemble average results.

Integrating global land-cover and soil datasets to update saturated hydraulic conductivity parameterization in hydrologic modeling.

Soil properties play an important role in watershed hydrology and environmental modeling. In order to model realistic hydrologic processes, it is necessary to obtain compatible soil data. This study introduces a new method that integrates global soil databases with land use/land cover (LULC) databases to better represent saturated hydraulic conductivity (Ks) which is one of the most important soil properties in hydrologic modeling. The Ks is modified by means of uniting physical infiltration mechanisms with hydrologic soil-LULC complexes from lookup tables from USDA-SCS (1985). This approach enables assimilation of available coarse resolution soil parameters by the finer resolution global LULC datasets. In order to test the performance of the proposed approach, it has been incorporated into the Watershed Environmental Hydrology (WEHY) model to simulate hydrologic conditions over the Cache Creek Watershed (CCW) and Shasta Dam Watershed (SDW) in Northern California by means of different soil datasets. Soil dataset S1 was obtained from the local soil database including SSURGO (Web soil survey, USDA). The second soil dataset (S2) is the global ISRIC soil data SoilGrids-1km obtained from World Soil Information. Soil dataset S4 is global FAO soil data. The third (S3) and fifth (S5) soil datasets were calculated by integrating the LULC into global soil datasets (S2, S4), respectively. The results of this study suggest that the proposed approach can provide a fine resolution soil dataset through integration of LULC and soil data, which can improve the estimation of soil hydraulic parameters and the performance of hydrologic modeling over the target watersheds. Within this framework, the new approach of this study can be applied widely in many parts of the world by means of the global soil and LULC databases.

Oxidative status and prolidase activities in generalized anxiety disorder.

OBJECTIVE: Prolidase (Pro), an intracellular enzyme necessary for collagen turnover, matrix remodelling and cell growth has been shown to be related to Oxidative Stress (OS). To our knowledge, serum Pro activity in generalized anxiety disorder (GAD) has not been documented yet. In this study, we aimed to evaluate OS and its relation with Pro activity in patients diagnosed with GAD. METHOD: Thirty untreated GAD patients and 30 healthy controls were included in the study. Blood samples were collected from all subjects to quantify total oxidant status (TOS), total antioxidant status (TAS) and Pro activity. Oxidative stress index (OSI), the ratio of TOS to TAS, is calculated to evaluate the balance between antioxidants and oxidants. Hamilton Anxiety Rating Scale (HARS) was used to determine the anxiety levels of all subjects. RESULTS: GAD group demonstrated statistically significantly higher TOS, OSI and Pro levels, when compared with the control group (t=2.947, p=0.005; t=2.874, p=0.006; and t=9.396, p<0.001 respectively). HARS scores were found to be positively correlated with TOS, OSI and Pro levels (p=0.008, r=0.338; p=0.008, r=0.339; and p<0.001, r=0.751 respectively). CONCLUSION: The degree of severity of OS is correlated with the levels of Pro. Thus, Pro might be the target enzyme, promising to be a marker for the follow-up of GAD patients. To the best of our knowledge, this study is the first to report a significant relation between Pro activity and GAD.

Trend analysis of watershed-scale precipitation over Northern California by means of dynamically-downscaled CMIP5 future climate projections.

The impacts of climate change on watershed-scale precipitation through the 21st century were investigated over eight study watersheds in Northern California based on dynamically downscaled CMIP5 future climate projections from three GCMs (CCSM4, HadGEM2-ES, and MIROC5) under the RCP4.5 and RCP8.5 future climate scenarios. After evaluating the modeling capability of the WRF model, the six future climate projections were dynamically downscaled by means of the WRF model over Northern California at 9km grid resolution and hourly temporal resolution during a 94-year period (2006-2100). The biases in the model simulations were corrected, and basin-average precipitation over the eight study watersheds was calculated from the dynamically downscaled precipitation data. Based on the dynamically downscaled basin-average precipitation, trends in annual depth and annual peaks of basin-average precipitation during the 21st century were analyzed over the eight study watersheds. The analyses in this study indicate that there may be differences between trends of annual depths and annual peaks of watershed-scale precipitation during the 21st century. Furthermore, trends in watershed-scale precipitation under future climate conditions may be different for different watersheds depending on their location and topography even if they are in the same region.

Assessment of 21st century drought conditions at Shasta Dam based on dynamically projected water supply conditions by a regional climate model coupled with a physically-based hydrology model.

Along with socioeconomic developments, and population increase, natural disasters around the world have recently increased the awareness of harmful impacts they cause. Among natural disasters, drought is of great interest to scientists due to the extraordinary diversity of their severity and duration. Motivated by the development of a potential approach to investigate future possible droughts in a probabilistic framework based on climate change projections, a methodology to consider thirteen future climate projections based on four emission scenarios to characterize droughts is presented. The proposed approach uses a regional climate model coupled with a physically-based hydrology model (Watershed Environmental Hydrology Hydro-Climate Model; WEHY-HCM) to generate thirteen equally likely future water supply projections. The water supply projections were compared to the current water demand for the detection of drought events and estimation of drought properties. The procedure was applied to Shasta Dam watershed to analyze drought conditions at the watershed outlet, Shasta Dam. The results suggest an increasing water scarcity at Shasta Dam with more severe and longer future drought events in some future scenarios. An important advantage of the proposed approach to the probabilistic analysis of future droughts is that it provides the drought properties of the 100-year and 200-year return periods without resorting to any extrapolation of the frequency curve.

Future climate change impact assessment of watershed scale hydrologic processes in Peninsular Malaysia by a regional climate model coupled with a physically-based hydrology modelo.

Impacts of climate change on the hydrologic processes under future climate change conditions were assessed over Muda and Dungun watersheds of Peninsular Malaysia by means of a coupled regional climate and physically-based hydrology model utilizing an ensemble of future climate change projections. An ensemble of 15 different future climate realizations from coarse resolution global climate models' (GCMs) projections for the 21st century was dynamically downscaled to 6km resolution over Peninsular Malaysia by a regional climate model, which was then coupled with the watershed hydrology model WEHY through the atmospheric boundary layer over Muda and Dungun watersheds. Hydrologic simulations were carried out at hourly increments and at hillslope-scale in order to assess the impacts of climate change on the water balances and flooding conditions in the 21st century. The coupled regional climate and hydrology model was simulated for a duration of 90years for each of the 15 realizations. It is demonstrated that the increase in mean monthly flows due to the impact of expected climate change during 2040-2100 is statistically significant from April to May and from July to October at Muda watershed. Also, the increase in mean monthly flows is shown to be significant in November during 2030-2070 and from November to December during 2070-2100 at Dungun watershed. In other words, the impact of the expected climate change will be significant during the northeast and southwest monsoon seasons at Muda watershed and during the northeast monsoon season at Dungun watershed. Furthermore, the flood frequency analyses for both watersheds indicated an overall increasing trend in the second half of the 21st century.

A high-speed area detector for novel imaging techniques in a scanning transmission electron microscope.

A scanning transmission electron microscope (STEM) produces a convergent beam electron diffraction pattern at each position of a raster scan with a focused electron beam, but recording this information poses major challenges for gathering and storing such large data sets in a timely manner and with sufficient dynamic range. To investigate the crystalline structure of materials, a 16x16 analog pixel array detector (PAD) is used to replace the traditional detectors and retain the diffraction information at every STEM raster position. The PAD, unlike a charge-coupled device (CCD) or photomultiplier tube (PMT), directly images 120-200keV electrons with relatively little radiation damage, exhibits no afterglow and limits crosstalk between adjacent pixels. Traditional STEM imaging modes can still be performed by the PAD with a 1.1kHz frame rate, which allows post-acquisition control over imaging conditions and enables novel imaging techniques based on the retained crystalline information. Techniques for rapid, semi-automatic crystal grain segmentation with sub-nanometer resolution are described using cross-correlation, sub-region integration, and other post-processing methods.

Idiopathic spontaneous coronary artery dissection: a case report.

Spontaneous coronary artery dissection frequently causes death, and most cases are diagnosed at autopsy. In most cases the affected persons are young pregnant females or women in the early postpartum period. We report a case of a female aged 36. She complained of acute chest pain and had ventricular fibrillation. She recovered after successful defibrillation. The coronary angiogram revealed dissection in the proximal left anterior descending artery. ST segment elevation was demonstrated on the electrocardiogram and the patient continued to have chest pains and underwent a coronary bypass operation. The etiology of spontaneous coronary artery dissection is still obscure and is mostly seen in young females. Early surgical intervention and stenting may save lives.

Sutureless vascular anastomoses by N-butyl-2 cyanoacrylate adhesive: an experimental animal study.

BACKGROUND: The purpose of this animal study was to find out whether sutureless anastomoses using N-butyl-2-cyanoacrylate were effective in the suppression of neointimal hyperplasia or not. MATERIAL AND METHODS: Ten male adult mongrel dogs were used in this animal study. The animals were randomly divided into a control group (n = 5) and a study group (n = 5). The study group underwent sutureless anastomoses using N-buthyl-2-cyanoacrylate adhesive. Infrarenal aortoaortic graft was interposed using polytetrafluoroethylene. RESULTS: In the study group, the mean intimal thickness at the proximal anastomosis was 27.4 +/- 1.94 microm and 27.4 +/- 1.51 microm at the distal anastomosis. In the control group, the mean intimal thickness was 138.4 +/- 5.02 mum at the proximal anastomosis and 67.6 +/- 6.42 microm at the distal anastomosis. Intimal thickness at the proximal and distal anastomoses in the control group was significantly (p < 0.001) greater than in the study group. Also, perianastomotic inflammation was more obvious in the control group compared to the study group (p < 0.01). CONCLUSION: Sutureless anastomoses using with N-butyl-2-cyanoacrylate adhesive might be a good alternative to conventional suture technique.

Analog pixel array detectors.

X-ray pixel array detectors (PADs) are generally thought of as either digital photon counters (DPADs) or X-ray analog-integrating pixel array detectors (APADs). Experiences with APADs, which are especially well suited for X-ray imaging experiments where transient or high instantaneous flux events must be recorded, are reported. The design, characterization and experimental applications of several APAD designs developed at Cornell University are discussed. The simplest design is a ;flash' architecture, wherein successive integrated X-ray images, as short as several hundred nanoseconds in duration, are stored in the detector chips for later off-chip digitization. Radiography experiments using a prototype flash APAD are summarized. Another design has been implemented that combines flash capability with the ability to continuously stream X-ray images at slower (e.g. milliseconds) rates. Progress is described towards radiation-hardened APADs that can be tiled to cover a large area. A mixed-mode PAD, design by combining many of the attractive features of both APADs and DPADs, is also described.

[Blunt injury of the aortic arch: report of two cases]. / Künt arkus aorta yaralanmasi iki olgu sunumu.

Blunt injury of the aortic arch and its great vessels is rare. Although most of the cases die at the event side, those who can reach the hospital present with a clinic of pseudoaneurysm or arterial occlusion. The mainstay of diagnosis is to have a high suspicion index. As the physical examination findings are subtle, radiodiagnostic tools are helpful. Aortography is the most important investigation technique in suitable cases in order to plan surgery. Extracorporeal circulation and deep hypothermia may successfully be used with known side effects. In this study, we report our recent experience with two cases of blunt injury of the arcus aorta.

Simple, high-yield purification of xanthine oxidase from bovine milk.

Xanthine oxidase, a commercially important enzyme with a wide area of application, was extracted from fresh milk, without added preservatives, using toluene and heat. The short purification procedure, with high yield, consisted of extraction, ammonium sulfate fractionation, and DEAE-Sepharose (fast flow) column chromatography. Xanthine oxidase was eluted as a single activity peak from the column using a buffer gradient. The purification fold, specific activity and yield for the purified xanthine oxidase were 328, 10.161 U/mg and 69%, respectively. The enzyme was concentrated by ultrafiltration, although 31% of the activity was lost during concentration, no change in specific activity was observed. Activity and protein gave coincident staining bands on native polyacrylamide gels. The intensity and the number of bands were dependent on the oxidative state(s) of the enzyme; reduction by 2-mercaptoethanol decreased the intensity of the slow-moving bands and increased the intensity of the fastest-moving band. Following sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), two major bands (molecular masses of 152 and 131 kDa) were observed, accounting for > or = 95% of xanthine oxidase. Native- and SDS-PAGE showed that the purified xanthine oxidase becomes a heterodimer due to endogenous proteases.