Ambient particulate matter and biomass burning: an ecological time series study of respiratory and cardiovascular hospital visits in northern Thailand.

BACKGROUND: Exposure to particulate matter (PM) emitted from biomass burning is an increasing concern, particularly in Southeast Asia. It is not yet clear how the source of PM influences the risk of an adverse health outcome. The objective of this study was to quantify and compare health risks of PM from biomass burning and non-biomass burning sources in northern Thailand. METHODS: We collected ambient air pollutant data (PM with a diameter of < 10 µm [PM10], PM2.5, Carbon Monoxide [CO], Ozone [O3], and Nitrogen Dioxide [NO2]) from ground-based monitors and daily outpatient hospital visits in Thailand during 2014-2017. Outpatient data included chronic lower respiratory disease (CLRD), ischaemic heart disease (IHD), and cerebrovascular disease (CBVD). We performed an ecological time series analysis to evaluate the association between daily air pollutants and outpatient visits. We used the 90th and 95th percentiles of PM10 concentrations to determine days of exposure to PM predominantly from biomass burning. RESULTS: There was significant intra annual variation in PM10 levels, with the highest concentrations occurring during March, coinciding with peak biomass burning. Incidence Rate Ratios (IRRs) between daily PM10 and outpatient visits were elevated most on the same day as exposure for CLRD = 1.020 (95% CI: 1.012 to 1.028) and CBVD = 1.020 (95% CI: 1.004 to 1.035), with no association with IHD = 0.994 (95% CI: 0.974 to 1.014). Adjusting for CO tended to increase effect estimates. We did not find evidence of an exposure response relationship with levels of PM10 on days of biomass burning. CONCLUSIONS: We found same-day exposures of PM10 to be associated with certain respiratory and cardiovascular outpatient visits. We advise implementing measures to reduce population exposures to PM wherever possible, and to improve understanding of health effects associated with burning specific types of biomass in areas where such large-scale activities occur.

Posterior fossa recurrence of WHO grade II and III supratentorial gliomas.

OBJECTIVE/BACKGROUND: Posterior fossa (PF) recurrences of supratentorial (ST) World Health Organization (WHO) grade II and III gliomas are thought to be rare and to have grim prognoses. METHODS: This study entailed searching through our database and reviewing the records of patients with grade II and III ST gliomas who developed PF recurrence with no overt secondary gliomatosis or leptomeningeal spread. RESULTS: Of 2266 grade II and III gliomas, 14 fulfilled the inclusion criteria: 5 oligodendrogliomas (O; 1 OII, 4 OIII); 7 astrocytomas (A; 4 AII, 3 AIII); and 2 oligoastrocytomas (OA; both OAIII). The male/female gender ratio was 10/4, and median age at recurrence was 43 years. Two groups were identified. In one group (n=8; 1 AII, 3 AIII, 2 OAIII, 2 OIII), a rapidly growing contrast-enhancing PF mass (6/8) was associated with ST progression, and median survival time after detection was only 6.5 months despite radiotherapy and/or chemotherapy. In the second group (n=6; 3 AII, 1 OII, and 2 OIII), a non-contrast-enhancing (5/6), asymptomatic (5/6), slow-growing PF mass remained isolated, and treatment with radio- or chemotherapy produced objective responses in three patients and durable stabilization in the remaining three. After a median follow-up of 63months, only one patient died due to delayed recurrence of the ST lesion, while the remaining five patients are still alive. CONCLUSION: Non-contiguous PF relapses of ST grade II and III gliomas are rare. A high-grade ST tumor that is concomitantly progressing appears to be a predictor of poor survival. Conversely, the tumor course may be indolent if the ST lesion is low-grade and non-progressive at the time of PF involvement. The possible mechanism(s) behind this tropism are also discussed.

Stroma AReactive Invasion Front Areas (SARIFA): a novel histopathologic biomarker in colorectal cancer patients and its association with the luminal tumour proportion.

BACKGROUND: Stroma AReactive Invasion Front Areas (SARIFA) is a novel prognostic histopathologic biomarker measured at the invasive front in haematoxylin & eosin (H&E) stained colon and gastric cancer resection specimens. The aim of the current study was to validate the prognostic relevance of SARIFA-status in colorectal cancer (CRC) patients and investigate its association with the luminal proportion of tumour (PoT). METHODS: We established the SARIFA-status in 164 CRC resection specimens. The relationship between SARIFA-status, clinicopathological characteristics, recurrence-free survival (RFS), cancer-specific survival (CSS), and PoT was investigated. RESULTS: SARIFA-status was positive in 22.6% of all CRCs. SARIFA-positivity was related to higher pT, pN, pTNM stage and high grade of differentiation. SARIFA-positivity was associated with shorter RFS independent of known prognostic factors analysing all CRCs (RFS: hazard ratio (HR) 2.6, p = 0.032, CSS: HR 2.4, p = 0.05) and shorter RFS and CSS analysing only rectal cancers. SARIFA-positivity, which was measured at the invasive front, was associated with PoT-low (p = 0.009), e.g., higher stroma content, and lower vessel density (p = 0.0059) measured at the luminal tumour surface. CONCLUSION: Here, we validated the relationship between SARIFA-status and prognosis in CRC patients and provided first evidence for a potential prognostic relevance in the subgroup of rectal cancer patients. Interestingly, CRCs with different SARIFA-status also showed histological differences measurable at the luminal tumour surface. Further studies to better understand the relationship between high luminal intratumoural stroma content and absence of a stroma reaction at the invasive front (SARIFA-positivity) are warranted and may inform future treatment decisions in CRC patients.

Analysis of CIC-associated CpG island methylation in oligoastrocytoma.

AIMS: Combined deletion of the whole chromosomal arms 1p and 19q is a frequent event in oligodendroglial tumours. Recent identification of recurrent mutations in CIC on 19q and FUBP1 on 1p and their mutational patterns suggest a loss of function of the respective proteins. Surprisingly, oligoastrocytomas harbouring identical genetic characteristics regarding 1p/19q codeletion and frequent IDH1/2 mutations have been shown to carry CIC mutations in a significantly lower number of cases. The present study investigates whether epigenetic modification may result in silencing of CIC. METHODS: As IDH1/2 mutation-mediated DNA hypermethylation is a prominent feature of these tumours, we analysed a set of CIC wild-type oligoastrocytomas and other diffuse gliomas with regard to 1p/19q status for presence of CIC-associated CpG island methylation by methylation-specific PCR. RESULTS: Both methylation-specific PCR and subsequent bisulphite-sequencing of selected cases revealed an unmethylated status in all samples. CONCLUSION: Despite the hypermethylator phenotype in IDH1/2 mutant tumours and recent detection of gene silencing particularly on retained alleles in oligodendroglial tumours, hypermethylation of CIC-associated CpG islands does not provide an alternative mechanism of functional CIC protein abrogation.

A class of selective antibacterials derived from a protein kinase inhibitor pharmacophore.

As the need for novel antibiotic classes to combat bacterial drug resistance increases, the paucity of leads resulting from target-based antibacterial screening of pharmaceutical compound libraries is of major concern. One explanation for this lack of success is that antibacterial screening efforts have not leveraged the eukaryotic bias resulting from more extensive chemistry efforts targeting eukaryotic gene families such as G protein-coupled receptors and protein kinases. Consistent with a focus on antibacterial target space resembling these eukaryotic targets, we used whole-cell screening to identify a series of antibacterial pyridopyrimidines derived from a protein kinase inhibitor pharmacophore. In bacteria, the pyridopyrimidines target the ATP-binding site of biotin carboxylase (BC), which catalyzes the first enzymatic step of fatty acid biosynthesis. These inhibitors are effective in vitro and in vivo against fastidious gram-negative pathogens including Haemophilus influenzae. Although the BC active site has architectural similarity to those of eukaryotic protein kinases, inhibitor binding to the BC ATP-binding site is distinct from the protein kinase-binding mode, such that the inhibitors are selective for bacterial BC. In summary, we have discovered a promising class of potent antibacterials with a previously undescribed mechanism of action. In consideration of the eukaryotic bias of pharmaceutical libraries, our findings also suggest that pursuit of a novel inhibitor leads for antibacterial targets with active-site structural similarity to known human targets will likely be more fruitful than the traditional focus on unique bacterial target space, particularly when structure-based and computational methodologies are applied to ensure bacterial selectivity.

A systematic review on regenerative alveolar graft materials in clinical trials: Risk of bias and meta-analysis.

BACKGROUND: Alveolar cleft grafting is a necessary procedure to restore bone defects. Randomized clinical trials (RCTs) are regarded as a golden standard for investigating the efficacy of treatments. Nevertheless, risk of bias (RoB) can still affect the validity of these trials. We aimed to conduct a systemic review of all control trials (CTs) using regenerative materials for alveolar cleft reconstructions to evaluate their RoB and perform a meta-analysis of new bone formation. METHODS: Cochrane Oral Health Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (PubMed), EMBASE AND Google Scholar were searched up to October 2020. Thereafter, the articles underwent quality assessment (according to the Jadad scale and the Delphi list) for the evaluation of the RoB. RESULTS: A total of 15 trials met the inclusion criteria, none of which reached a full score. Of these, 20% didn't randomize the trails, 73,33% failed to describe the way of randomization, and none reported the double-blinded criteria. Furthermore, allocation concealment (99.9%), intention to treat (100%), and patient awareness (100%) were inadequately described. The meta-analysis found no significant difference between regenerative materials and iliac crest graft. CONCLUSION: This review showed high RoB in CTs implying quality improvement of CTs is necessary. Meta-analysis showed no significant difference between the regenerative materials and autogenous grafts.

Radio-Pathomic Maps of Cell Density Identify Brain Tumor Invasion beyond Traditional MRI-Defined Margins.

BACKGROUND AND PURPOSE: Currently, contrast-enhancing margins on T1WI are used to guide treatment of gliomas, yet tumor invasion beyond the contrast-enhancing region is a known confounding factor. Therefore, this study used postmortem tissue samples aligned with clinically acquired MRIs to quantify the relationship between intensity values and cellularity as well as to develop a radio-pathomic model to predict cellularity using MR imaging data. MATERIALS AND METHODS: This single-institution study used 93 samples collected at postmortem examination from 44 patients with brain cancer. Tissue samples were processed, stained with H&E, and digitized for nuclei segmentation and cell density calculation. Pre- and postgadolinium contrast T1WI, T2 FLAIR, and ADC images were collected from each patient's final acquisition before death. In-house software was used to align tissue samples to the FLAIR image via manually defined control points. Mixed-effects models were used to assess the relationship between single-image intensity and cellularity for each image. An ensemble learner was trained to predict cellularity using 5 × 5 voxel tiles from each image, with a two-thirds to one-third train-test split for validation. RESULTS: Single-image analyses found subtle associations between image intensity and cellularity, with a less pronounced relationship in patients with glioblastoma. The radio-pathomic model accurately predicted cellularity in the test set (root mean squared error = 1015 cells/mm2) and identified regions of hypercellularity beyond the contrast-enhancing region. CONCLUSIONS: A radio-pathomic model for cellularity trained with tissue samples acquired at postmortem examination is able to identify regions of hypercellular tumor beyond traditional imaging signatures.

Artificial intelligence for detection of microsatellite instability in colorectal cancer-a multicentric analysis of a pre-screening tool for clinical application.

BACKGROUND: Microsatellite instability (MSI)/mismatch repair deficiency (dMMR) is a key genetic feature which should be tested in every patient with colorectal cancer (CRC) according to medical guidelines. Artificial intelligence (AI) methods can detect MSI/dMMR directly in routine pathology slides, but the test performance has not been systematically investigated with predefined test thresholds. METHOD: We trained and validated AI-based MSI/dMMR detectors and evaluated predefined performance metrics using nine patient cohorts of 8343 patients across different countries and ethnicities. RESULTS: Classifiers achieved clinical-grade performance, yielding an area under the receiver operating curve (AUROC) of up to 0.96 without using any manual annotations. Subsequently, we show that the AI system can be applied as a rule-out test: by using cohort-specific thresholds, on average 52.73% of tumors in each surgical cohort [total number of MSI/dMMR = 1020, microsatellite stable (MSS)/ proficient mismatch repair (pMMR) = 7323 patients] could be identified as MSS/pMMR with a fixed sensitivity at 95%. In an additional cohort of N = 1530 (MSI/dMMR = 211, MSS/pMMR = 1319) endoscopy biopsy samples, the system achieved an AUROC of 0.89, and the cohort-specific threshold ruled out 44.12% of tumors with a fixed sensitivity at 95%. As a more robust alternative to cohort-specific thresholds, we showed that with a fixed threshold of 0.25 for all the cohorts, we can rule-out 25.51% in surgical specimens and 6.10% in biopsies. INTERPRETATION: When applied in a clinical setting, this means that the AI system can rule out MSI/dMMR in a quarter (with global thresholds) or half of all CRC patients (with local fine-tuning), thereby reducing cost and turnaround time for molecular profiling.

'Magic' nucleus 42Si.

Nuclear shell structures--the distribution of the quantum states of individual protons and neutrons--provide one of our most important guides for understanding the stability of atomic nuclei. Nuclei with 'magic numbers' of protons and/or neutrons (corresponding to closed shells of strongly bound nucleons) are particularly stable. Whether the major shell closures and magic numbers change in very neutron-rich nuclei (potentially causing shape deformations) is a fundamental, and at present open, question. A unique opportunity to study these shell effects is offered by the 42Si nucleus, which has 28 neutrons--a magic number in stable nuclei--and 14 protons. This nucleus has a 12-neutron excess over the heaviest stable silicon nuclide, and has only one neutron fewer than the heaviest silicon nuclide observed so far. Here we report measurements of 42Si and two neighbouring nuclei using a technique involving one- and two-nucleon knockout from beams of exotic nuclei. We present strong evidence for a well-developed proton subshell closure at Z = 14 (14 protons), the near degeneracy of two different (s(1/2) and d(3/2)) proton orbits in the vicinity of 42Si, and a nearly spherical shape for 42Si.

Hemangiopericytomas grade II are not benign tumors.

BACKGROUND: Hemangiopericytomas (HPs) of the central nervous system are rare tumors and afflicted with a high propensity of recurrences and metastases. Histopathologically, HPs correspond to differentiated (WHO grade II) and anaplastic (WHO grade III) tumors. With respect to the available literature and our own experiences, the aggressiveness, especially of differentiated grade II HPs, seems to be underestimated. METHODS: Thus, in this retrospective study, we describe tumor behavior and examined the effect of radio- and chemotherapy on tumor control with respect to the WHO classification of grade II and III neoplasms. This study consists of 15 patients with cerebral (n = 10) and spinal (n = 5) HPs. RESULTS: Seven HPs were histopathologically classified as grade II and eight as anaplastic grade III tumors. Complete surgical resection could be achieved in 60% of cerebral and in 25% of spinal HPs. In total, local recurrences occurred in 20% of patients within 17.3 months after the primary operation. Recurrences occurred both from differentiated (n = 1) and anaplastic (n = 2) neoplasms. Treatment comprised re-operation followed by radio- and chemotherapy. Pointing out the importance of the extent of surgical resection, in this study, we could not detect a single patient showing any recurrences or systemic metastases after complete surgical resection of grade II HPs. During primary diagnostics, four patients showed systemic metastases. Although these tumors could be controlled via surgery, systemic metastases appeared in further four patients within 60.4 months. Interestingly, two of them were classified as differentiated tumors (WHO grade II). To control tumor progress, radiotherapy seemed to be partially effective. On the other hand, however, chemotherapy did not show any effect on tumor control. With respect to these results, screening investigations seem to be indispensable and are highly recommended during primary diagnostics and after the appearance of recurrences or metastases, independent of the histopathological staging of the tumor. CONCLUSION: With respect to our results, radical surgical resection offers the best treatment option to control tumor progress. In case of subtotal resection or histopathologically diagnosed anaplasia (WHO III), radiotherapy seems to be indicated; however, chemotherapy did not show effectiveness to control tumor progress.

[Freshwater sponge silicateins: comparison of sequences and exon-intron structure of genes].

Siliceous sponge spicules contain silicateins--proteins taking part in biogenic silica precipitation and determination of the spicule morphological features. The exon-intron structure of four silicatein-alpha isoforms: -alpha1,-alpha2, -alpha3 and -alpha4 from endemic baikalian sponge Lubomirskia baicalensis was studied. For eight sponge species, including both cosmopolitan (Spongilla lacustris, Ephydatia muelleri, E. fluviatilis) and Baikal endemic (L. baicalensis, L. incrustans, Baikalospongia intermedia, B. fungiformis, Sw. papyracea) species, seventeen gene fragment sequences of different silicatein isoforms were determined. It was shown that cosmopolitan and endemic Baikalian sponges differ from each other by gene structure (have different length ofintrons). Among Baikalian sponges silicatein-alpha1 has the most variable intron length, and silicatein-alpha4 is the most conservative. Phylogenetic analysis of amino-acid silicatein sequences allow identify different silicatein isoforms, which authentically differ form four clusters on phylogenetic tree. Phylogenetic analysis of exon-intron sequences gives the possibility to separate different sponge species in the clusters.

Influence of preparation form, luting space setting and cement type on the marginal and internal fit of CAD/CAM crown copings.

PURPOSE: To evaluate the influence of two different tooth preparation forms, two luting space settings and two cement types on the marginal and internal adaptation of all-ceramic crown copings produced using Cerec3 CAD/CAM system. MATERIALS AND METHODS: Forty working stone dies were made from two metal master casts (1. Tooth 36: with anatomic occlusal reduction, 2. Tooth 36: with flat occlusal reduction). Forty crown copings were milled using Vita In-Ceram 2000 YZ: 20 with an luting space settings of 0 = 100 microm and 20 with -50 = 50 microm. Copings were cemented using two cements (zinc phosphate cement, P21: Panavia21), then embedded and sectioned bucco-lingually and mesio-distally. Widths of marginal and internal gaps were measured using a light microscope at magnification of 40X. Data were submitted to one-way ANOVA, and statistical significance was set at p < 0.05. RESULTS: Copings with flat occlusal reduction and luting space settings of 100 pm had a better internal and marginal fit compared with copings with anatomic occlusal reduction and luting space settings of 50 microm, regardless of the cement used. P21 showed a significantly better fit compared with zinc phosphate cement. CONCLUSION: The presented Cerec3 CAD/CAM system can provide a marginal and internal adaptation which is comparable to that of conventional cast and conventional all-ceramic crowns.

The proportion of tumour cells is an independent predictor for survival in colorectal cancer patients.

BACKGROUND: The proportion of epithelial and stromal cells in tumours is thought to have an important role in the progression of epithelial malignancy. We aimed to determine whether the relative proportion of tumour (PoT) was related to survival in colorectal cancer. METHODS: The PoT at the luminal surface was measured by point counting using virtual tissue sections in a series of 145 colorectal cancer cases. The relationship of PoT to clinicopathological parameters including cancer-specific survival was analysed. Modified receiver operating characteristic curves were used to determine the optimum cut off points to dichotomise the data for survival analyses. RESULTS: Tumours with PoT-low (

Carbonic anhydrase and osteoclasts: localization by labeled inhibitor autoradiography.

Autoradiography with tritiated acetazolamide indicates that osteoclasts of the hen and chick contain concentrations of carbonic anhydrase which are similar to those in pancreatic acinar cells. Grain counts of osteoblasts and osteocytes were not different from background. Thus, a sufficient quantity of carbonic anhydrase seems to be present in osteoclasts to be of physiological importance in bone resorption.

"Polywater": a hydrosol?

Measurements of the dielectric constant and the effective parallel conductance of a specimen of anomalous water suggest that anomalous water is a hydrosol consisting of finely divided particulate matter suspended in ordinary water. Scanning electron micrography confirms the presence of particulate matter. These new experimental data provide an alternative explanation for the properties of anomalous water.

HTLV-III/LAV-neutralizing antibodies to an E. coli-produced fragment of the virus envelope.

Immunization with either an Escherichia coli recombinant segment of the human T-cell lymphotropic virus (HTLV-III/LAV) envelope protein (gp 120) or with deglycosylated gp 120 envelope protein produced antibodies that neutralize HTLV-III/LAV infection in vitro. Virus neutralization titers of these antisera were equivalent to those obtained with purified native gp120 as immunogen. This localizes at least one class of neutralizing epitopes to the carboxyl-terminal half of the molecule. In addition, native gp120 prevented HTLV-III/LAV--mediated cell fusion, whereas the recombinant gp120 fragment did not. This shows that although glycosylation is not required for induction of neutralizing antibodies, it may be important for interaction with CD4, the virus receptor. A segment of the HTLV-III/LAV envelope produced in E. coli may be an important ingredient of a vaccine for acquired immune deficiency syndrome.

Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition.

MEK1 and MEK2 are closely related, dual-specificity tyrosine/threonine protein kinases found in the Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway. Approximately 30% of all human cancers have a constitutively activated MAPK pathway, and constitutive activation of MEK1 results in cellular transformation. Here we present the X-ray structures of human MEK1 and MEK2, each determined as a ternary complex with MgATP and an inhibitor to a resolution of 2.4 A and 3.2 A, respectively. The structures reveal that MEK1 and MEK2 each have a unique inhibitor-binding pocket adjacent to the MgATP-binding site. The presence of the potent inhibitor induces several conformational changes in the unphosphorylated MEK1 and MEK2 enzymes that lock them into a closed but catalytically inactive species. Thus, the structures reported here reveal a novel, noncompetitive mechanism for protein kinase inhibition.

Downregulation of RUNX3 and TES by hypermethylation in glioblastoma.

Glioblastoma, the most aggressive and least treatable form of malignant glioma, is the most common human brain tumor. Although many regions of allelic loss occur in glioblastomas, relatively few tumor suppressor genes have been found mutated at such loci. To address the possibility that epigenetic alterations are an alternative means of glioblastoma gene inactivation, we coupled pharmacological manipulation of methylation with gene profiling to identify potential methylation-regulated, tumor-related genes. Duplicates of three short-term cultured glioblastomas were exposed to 5 microM 5-aza-dC for 96 h followed by cRNA hybridization to an oligonucleotide microarray (Affymetrix U133A). We based candidate gene selection on bioinformatics, reverse transcription-polymerase chain reaction (RT-PCR), bisulfite sequencing, methylation-specific PCR and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Two genes identified in this manner, RUNX3 and Testin (TES), were subsequently shown to harbor frequent tumor-specific epigenetic alterations in primary glioblastomas. This overall approach therefore provides a powerful means to identify candidate tumor-suppressor genes for subsequent evaluation and may lead to the identification of genes whose epigenetic dysregulation is integral to glioblastoma tumorigenesis.

Differential mobility separation of ions using a rectangular asymmetric waveform.

The performance of a planar differential mobility spectrometer (DMS) is investigated when operated in air at ambient pressure and driven by a rectangular asymmetric waveform, limited to frequencies of <1.2 MHz and voltage pulse amplitudes of <1 kV with steep rise times of the order of approximately 15 ns. Independent control of frequency, voltage pulse amplitude, and duty cycle allow for characterizing the DMS in terms of transmission, resolution and separation. The tradeoff between sensitivity and resolution and the effect of duty cycle on instrument performance are demonstrated experimentally. The dependence of ion mobility on the magnitude of the electric field determines the displacement of ions measured by the DC compensation voltage as a function of the duty cycle. Optimum values for the duty cycle exist for the separation of A- and C-type ions, while, B-type ions exhibit a more complex behavior. An analytical expression for describing the effect of duty cycle on the separation of the ions, determined by variations in the compensation voltage, is developed and compared to experimental results obtained in air below 75 Td using estimated alpha parameters for a set of ketones. In this context, errors associated with the calculation of alpha parameters using polynomials of even powers are highlighted.

Use of a single bipolar electrode in the posterior arytenoid muscles for bilateral monitoring of the recurrent laryngeal nerves in thyroid surgery.

The aims were to assess the technical feasibility of using a single electrode in the posterior arytenoid muscles (PAM) for intraoperative monitoring of the recurrent laryngeal nerve (RLN) in thyroid surgery, to validate the new method against the insertion of electrodes placed in the vocal cord muscle, and to report the results of the clinical application of the new concept. A total of 52 patients were enrolled. The handling and safety of RLN monitoring was tested by simultaneous registration of the EMG response from vocal fold electrodes and PAM electrodes. Acoustically and electromyographically we found nearly the same values for the arytenoid muscles as for the vocal folds, although the signals taken from the vocal folds were slightly stronger. PAM recording using a single bipolar electrode is technically feasible and as reliable compared to the standard vocal cord monitoring.