Mammalian SWI/SNF complex activity regulates POU2F3 and constitutes a targetable dependency in small cell lung cancer.

Small cell lung cancers (SCLCs) are composed of heterogeneous subtypes marked by lineage-specific transcription factors, including ASCL1, NEUROD1, and POU2F3. POU2F3-positive SCLCs, ∼12% of all cases, are uniquely dependent on POU2F3 itself; as such, approaches to attenuate POU2F3 expression may represent new therapeutic opportunities. Here using genome-scale screens for regulators of POU2F3 expression and SCLC proliferation, we define mSWI/SNF complexes as top dependencies specific to POU2F3-positive SCLC. Notably, chemical disruption of mSWI/SNF ATPase activity attenuates proliferation of all POU2F3-positive SCLCs, while disruption of non-canonical BAF (ncBAF) via BRD9 degradation is effective in pure non-neuroendocrine POU2F3-SCLCs. mSWI/SNF targets to and maintains accessibility over gene loci central to POU2F3-mediated gene regulatory networks. Finally, clinical-grade pharmacologic disruption of SMARCA4/2 ATPases and BRD9 decreases POU2F3-SCLC tumor growth and increases survival in vivo. These results demonstrate mSWI/SNF-mediated governance of the POU2F3 oncogenic program and suggest mSWI/SNF inhibition as a therapeutic strategy for POU2F3-positive SCLCs.

Mammalian SWI/SNF complex activity regulates POU2F3 and constitutes a targetable dependency in small cell lung cancer.

Small cell lung cancers (SCLC) are comprised of heterogeneous subtypes marked by lineage-specific transcription factors, including ASCL1, NEUROD1, and POU2F3. POU2F3-positive SCLC, ∼12% of all cases, are uniquely dependent on POU2F3 itself; as such, approaches to attenuate POU2F3 expression may represent new therapeutic opportunities. Here using genome-scale screens for regulators of POU2F3 expression and SCLC proliferation, we define mSWI/SNF complexes, including non-canonical BAF (ncBAF) complexes, as top dependencies specific to POU2F3-positive SCLC. Notably, clinical-grade pharmacologic mSWI/SNF inhibition attenuates proliferation of all POU2F3-positive SCLCs, while disruption of ncBAF via BRD9 degradation is uniquely effective in pure non-neuroendocrine POU2F3-SCLCs. mSWI/SNF maintains accessibility over gene loci central to POU2F3-mediated gene regulatory networks. Finally, chemical targeting of SMARCA4/2 mSWI/SNF ATPases and BRD9 decrease POU2F3-SCLC tumor growth and increase survival in vivo . Taken together, these results characterize mSWI/SNF-mediated global governance of the POU2F3 oncogenic program and suggest mSWI/SNF inhibition as a therapeutic strategy for SCLC.

Hierarchical Mn3O4/NiSe2-MnSe2: A Versatile Electrode Material for High-Performance All-Solid-State Hybrid Pseudocapacitors with Supreme Working Durability.

As highly efficient electrochemical energy storage devices are in indispensable demand for numerous modern-day technologies, herein sluggish precipitation followed by an anion exchange procedure has been developed to synthesize an oxide-selenide mixed phase (Mn3O4/NiSe2-MnSe2) novel electrode material with high surface area and porosity for high-performance all-solid-state hybrid pseudocapacitors (ASSHPC). Mn3O4/NiSe2-MnSe2 shows a rich Tyndall effect (in H2O) and possesses randomly arranged low-dimensional crystallites of nearly similar size and uniform shape. The electrochemical analyses of Mn3O4/NiSe2-MnSe2 corroborate good electrochemical reversibility during charge transfer, superior pseudocapacitive charge-storage efficiency, and very low charge transfer and series resistance, ion-diffusion resistance, and relaxation time, which endorse the quick pseudocapacitive response of the material. The Mn3O4/NiSe2-MnSe2||N-rGO ASSHPC device demonstrates excellent charge-storage physiognomies suggestive of rich electrochemical and electromicrostructural compatibility between the electrode materials in the fabricated assembly. The Mn3O4/NiSe2-MnSe2||N-rGO ASSHPC device delivers high mass and area specific capacitance/capacity, very low charge-transfer resistance (∼0.74 Ω), total series resistance (∼0.76 Ω), diffusion resistance, and a relaxation time constant, which endorse the quick pseudocapacitive response of the device. The device delivers higher energy and power density (∼34 W h kg-1 at ∼2994 W kg-1), rate efficiency (∼17 W h kg-1 at ∼11,995 W kg-1), and cyclic performance (∼97.2% specific capacity/capacitance retention after 9500 continuous GCD cycles). The superior Ragone and cyclic efficiencies of the ASSHPC device are ascribed to the multiple redox-active Ni and Mn ions which lead to the supplemented number of redox reactions; "electroactive-ion buffering pool"-like physiognomics of Mn3O4/NiSe2-MnSe2, which facilitate the electrolyte ion dissemination to the electroactive sites even at high rate redox condition; and ideal electro-microstructural compatibility between the electrode materials, which leads to assisted charge transfer and absolute ion dissemination during the charge-storage process.

Downscaling Global Gridded Crop Yield Data Products and Crop Water Productivity Mapping Using Remote Sensing Derived Variables in the South Asia.

Local scale crop yield and crop water productivity information is critical for informed decision making, crop yield forecasting and crop model calibration applications. In this study, we have attempted to downscale coarse resolution primary season rice yield datasets to a local scale of 500 m using a minimum-median downscaling approach. Sixteen mainland countries in south and southeast Asia region were considered as study region to downscale global rice yield datasets for 2000-2015. Four medium resolution remote sensing derived vegetation indices such as Normalised Difference Vegetation Index (NDVI), Enhanced Vegetation Index (EVI), Leaf Area Index (LAI), and Gross Primary Product (GPP) were used to downscale coarse resolution global rice yield datasets. A kharif season district level rice yield data from International Crops Research Institute for the Semi-Arid Tropics (ICRISAT), India was used as a reference dataset to evaluate the downscaled rice yields at the district scale. The proposed downscaling approach performance was satisfactory with a mean absolute error (MAE) range of 0.85-1.2 t/ha which lies in the error range of 10-15% with respect to actual range of reference rice yield datasets. Furthermore, crop water productivity maps at 500 m scale were also developed with the downscaled rice yield and Moderate Resolution Imaging Spectroradiometer (MODIS) Evapotranspiration (ET) data products. Statistical analysis shows that the rice yield and crop water productivity values across different climate zones were statistically significant. Tropical zone-based crop yield and crop water productivity values were showing higher variation when compared to other climate zones with a range of 1-10 t/ha and 1-12.5 kg/m3, respectively. Supplementary Information: The online version contains supplementary material available at 10.1007/s42106-022-00223-2.

Evaluation and comparison of performance of low-dose 128-slice CT scanner with different mAs values: A phantom study.

OBJECTIVE: Radiation dose in computed tomography (CT) has been the concern of physicists ever since the introduction of CT scan. The objective of this study was to evaluate the performance of low-dose 128-slice CT scanner with different mAs values. MATERIALS AND METHODS: Quantitative study was carried out at different values of mAs. Philips brilliance CT phantom with Philips ingenuity 128-slice low-dose CT scanner was chosen for this study. CT number linearity, CT number accuracy, slice thickness accuracy, high-contrast resolution, and low-contrast resolution were calculated and estimated computed tomography dose index volume (CTDIvol) for all the mAs values were recorded. Noise was calculated for all mAs values for comparison. RESULTS: Data analysis shows that image quality was acceptable for all protocols. High-contrast resolution for all protocols was 20 line pairs per centimeter. Low-contrast resolution for 50 mAs images was 4 mm and 3 mm for other mAs protocols. Images acquired using 100 mAs revealed ring artifacts. CTDIvol using 50 mAs was 33% of the CTDIvol using 150 mAs. The dose-length product at 100 mAs was reduced to 66% of the dose-length product at 150 mAs, and the same at 50 mAs was reduced to 33%. CONCLUSION: It is evident here that mAs has direct impact on the radiation dose to patient. With iDose4, mAs can be reduced to 50 mAs in multislice low-dose CT scan to reduce the radiation dose with minimal effect on image quality for slice thickness 4 mm. However, noise would dominate at tube current lower than 50 mAs for 120 kVp.

Outcomes With Early Cardiac Catheterization in Out of Hospital Cardiac Arrest Survivors and Utility of a Prognostic Scoring System.

Objectives A retrospective study in patients presenting out of hospital cardiac arrest (OHCA) to assess the impact of early cardiac catheterization on survival and cerebral performance category (CPC) on discharge. Background The role of early coronary angiography in OHCA patients remains controversial. The cardiac arrest hospital prognosis (CAHP) scoring system has not been validated in the US population. Methods Inclusion criteria were OHCA patients with a sustained return of spontaneous circulation (ROSC), presumed cardiac cause of arrest, and elements to calculate CAHP score. We compared in-hospital mortality rates and final inpatient CPC in patients who underwent early cardiac catheterization to those with delayed or no cardiac catheterization. We assessed the performance of the CAHP score in the entire OHCA population using receiver-operator curve (ROC) analysis. Results A hundred and fifty-eight patients were included, of which 39 underwent early cardiac catheterization. The mortality rate of the early catheterization group was lower than the delayed or no catheterization group (41% vs 61.3%, p=0.02); the Early cardiac catheterization group had more favorable final hospital CPC scores overall (53.8% vs 24.3%, p<0.001). However, when risk-adjusted, there was no benefit in early catheterization for mortality or CPC level in any of the CAHP score subgroups. CAHP scores showed good discrimination with c-statistics of 0.85 for mortality and 0.90 for the CPC category. Conclusion Early use of cardiac catheterization in OHCA patients with sustained ROSC was not associated with lower mortality rates or higher rates of favorable neurologic recovery when adjusted for baseline risk factors in each of the different CAHP score-based sub-groups. This was despite a higher proportion of patients with STEMI in the early catheterization group. We demonstrated a good fit between observed outcomes and outcomes predicted by the CAHP scoring system.

Raman Spectroscopy Can Distinguish Glyphosate-Susceptible and -Resistant Palmer Amaranth (Amaranthus palmeri).

The non-judicious use of herbicides has led to a widespread evolution of herbicide resistance in various weed species including Palmer amaranth, one of the most aggressive and troublesome weeds in the United States. Early detection of herbicide resistance in weed populations may help growers devise alternative management strategies before resistance spreads throughout the field. In this study, Raman spectroscopy was utilized as a rapid, non-destructive diagnostic tool to distinguish between three different glyphosate-resistant and four -susceptible Palmer amaranth populations. The glyphosate-resistant populations used in this study were 11-, 32-, and 36-fold more resistant compared to the susceptible standard. The 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) gene copy number for these resistant populations ranged from 86 to 116. We found that Raman spectroscopy could be used to differentiate herbicide-treated and non-treated susceptible populations based on changes in the intensity of vibrational bands at 1156, 1186, and 1525 cm-1 that originate from carotenoids. The partial least squares discriminant analysis (PLS-DA) model indicated that within 1 day of glyphosate treatment (D1), the average accuracy of detecting herbicide-treated and non-treated susceptible populations was 90 and 73.3%, respectively. We also found that glyphosate-resistant and -susceptible populations of Palmer amaranth can be easily detected with an accuracy of 84.7 and 71.9%, respectively, as early as D1. There were relative differences in the concentration of carotenoids in plants with different resistance levels, but these changes were not significant. The results of the study illustrate the utility of Raman spectra for evaluation of herbicide resistance and stress response in plants under field conditions.

Use of Laser in Sleep Disorders: A Review on Low Laser Uvulopalatoplasty.

METHODS: A comprehensive and systematic literature review was conducted using PubMed, Google Scholar, Cochrane Central Register of Controlled Trials, Embase, Web of Science, the US National Institutes of Health Trials Registry, WHO Library, and Medline. The search strategies were developed to cover publications from January 2010 through March 2020. The past 10 years of the search were performed to report the data following systematic review and meta-analysis protocol (PRISMA-P) 2015 statement. RESULTS: With the help of keywords, the total number of abstracts identified was 946. These abstracts were further reviewed as per inclusion and exclusion criteria, and 106 abstracts were identified to match the selection criteria. Further review of full articles resulted in 12 articles that matched the inclusion criteria for the study. CONCLUSION: Er:YAG can be a good alternative and least invasive therapy for managing snoring and obstructive sleep apnea. Er:YAG therapy is considered to nonsurgical intervention with minimum side effects and can be performed chairside.

The oncogenicity of tumor-derived mutant p53 is enhanced by the recruitment of PLK3.

p53 mutations with single amino acid changes in cancer often lead to dominant oncogenic changes. Here, we have developed a mouse model of gain-of-function (GOF) p53-driven lung cancer utilizing conditionally active LSL p53-R172H and LSL K-Ras-G12D knock-in alleles that can be activated by Cre in lung club cells. Mutation of the p53 transactivation domain (TAD) (p53-L25Q/W26S/R172H) eliminating significant transactivation activity resulted in loss of tumorigenicity, demonstrating that transactivation mediated by or dependent on TAD is required for oncogenicity by GOF p53. GOF p53 TAD mutations significantly reduce phosphorylation of nearby p53 serine 20 (S20), which is a target for PLK3 phosphorylation. Knocking out PLK3 attenuated S20 phosphorylation along with transactivation and oncogenicity by GOF p53, indicating that GOF p53 exploits PLK3 to trigger its transactivation capability and exert oncogenic functions. Our data show a mechanistic involvement of PLK3 in mutant p53 pathway of oncogenesis.

Optimal Use of a Panoramic Radiograph as a Screening Tool for Condylar Resorption in Patients Undergoing Active Orthodontic Treatment: A Case Series.

Condylar resorption of temporomandibular joint findings in the panoramic radiographs is an indication of bone resorption suggesting possible degenerative joint disease that warrants early screen and subsequent referral to a dedicated specialist. This case series reports three patients that underwent the active orthodontic treatment for the duration of approximately 24-36 months. The patients were asymptomatic at the initial examination. The clinical examination was negative for clicking; the range of motion on opening, lateral excursion, and protrusion was normal. Neither of these patients had a history of rheumatic disease or bruxism. During the later stages of orthodontic treatment, two of the three patients reported mild pain and clicking during mastication, which was also confirmed chairside on clinical evaluation. Patients were referred to the orofacial pain specialist, were they were prescribed specific medication for the symptoms, along with cognitive behavioral therapy, and were further evaluated for splint therapy. Panoramic radiographs taken before the start of the treatment, during the treatment and at the completion of the orthodontic treatments indicate the progression in the resorption of mandibular condyle in all three patients suggesting possible degeneration that warrants further investigation and therapy.

Symbiotic nitrogen fixation and endophytic bacterial community structure in Bt-transgenic chickpea (Cicer arietinum L).

Symbiotic nitrogen fixation (SNF) of transgenic grain legumes might be influenced either by the site of transgene integration into the host genome or due to constitutive expression of transgenes and antibiotic-resistant marker genes. The present investigation confirmed proper nodulation of five tested Bt-chickpea events (IPCa2, IPCa4, IPCT3, IPCT10, and IPCT13) by native Mesorhizobium under field environment. Quantitative variations for nodulation traits among Bt-chickpea were determined and IPCT3 was found superior for nodule number and nodule biomass. Diversity, as well as richness indices, confirmed the changes in bacterial community structure of root and root-nodules from Bt-chickpea events IPCa2 and IPCT10. Especially, Gram-positive bacteria belonging to Firmicutes and Actinobacteria were selectively eliminated from root colonization of IPCa2. Richness indices (CHAO1 and ACE) of the root-associated bacterial community of IPCa2 was 13-14 times lesser than that of parent cv DCP92-3. Root nodule associated bacterial community of IPCT10 was unique with high diversity and richness, similar to the roots of non-Bt and Bt-chickpea. It indicated that the root nodules of IPCT10 might have lost their peculiar characteristics and recorded poor colonization of Mesorhizobium with a low relative abundance of 0.27. The impact of Bt-transgene on bacterial community structure and nodulation traits should be analyzed across the years and locations to understand and stabilize symbiotic efficiency for ecosystem sustainability.

Marijuana-Derived Cannabinoids Trigger a CB2/PI3K Axis of Suppression of the Innate Response to Oral Pathogens.

Cannabis use is an emergent risk factor for periodontitis, a chronic bacterial-induced disease of the supporting structures of the teeth. However, the mechanisms by which marijuana exposure predisposes to periodontal tissue destruction have yet to be elucidated. Therefore, we examined the influence of physiologically relevant doses of major marijuana-derived phytocannabinoid subtypes (cannabidiol [CBD]; cannabinol [CBN]; and tetrahydrocannabinol [THC], 1.0 µg/ml) on the interactions of three ultrastructurally variant oral pathogens, Porphyromonas gingivalis, Filifactor alocis, and Treponema denticola with the immune system. CBD, CBN, and THC each suppressed P. gingivalis-induced IL-12 p40, IL-6, IL-8, and TNF release while enhancing the anti-inflammatory cytokine, IL-10, from human innate cells. Similar phenomena were observed in F. alocis- and T. denticola-exposed human monocytes and human gingival keratinocytes. Higher phytocannabinoid doses (≥5.0 µg/ml) compromised innate cell viability and inhibited the growth of P. gingivalis and F. alocis, relative to unexposed bacteria. T. denticola, however, was resistant to all cannabinoid doses tested (up to 10.0 µg/ml). Pharmaceutical inhibition and efficient gene silencing indicated that a common CB2/PI3K axis of immune suppression is triggered by phytocannabinoids in vitro. This pathway does not appear to perpetuate through the canonical GSK3ß-dependent cholinergic anti-inflammatory pathway, the predominant endogenous inflammatory control system. In a repetitive, transient oral infection model, CBD also suppressed P. gingivalis-induced innate immune markers in wild-type mice, but not in CB2-/- mice. If such phenomena occur in humans in situ, environmental cannabinoids may enhance periodontitis via direct toxic effects on specific oral bacteria; by compromising innate cell vitality; and/or through a suppressed innate response to periodontal pathogens involving a CB2/PI3K signaling lineage.

DNA replication in progenitor cells and epithelial regeneration after lung injury requires the oncoprotein MDM2.

Depletion of epithelial cells after lung injury prompts proliferation and epithelial mesenchymal transition (EMT) of progenitor cells, and this repopulates the lost epithelial layer. To investigate the cell proliferative function of human oncoprotein MDM2, we generated mouse models targeting human MDM2 expression in either lung Club or alveolar cells after doxycycline treatment. We report that MDM2 expression in lung Club or alveolar cells activates DNA replication specifically in lung progenitor cells only after chemical- or radiation-induced lung injury, irrespective of their p53 status. Activation of DNA replication by MDM2 triggered by injury leads to proliferation of lung progenitor cells and restoration of the lost epithelial layers. Mouse lung with no Mdm2 allele loses its ability to replicate DNA, whereas loss of 1 Mdm2 allele compromises this function, demonstrating the requirement of endogenous MDM2. We show that the p53-independent ability of MDM2 to activate Akt signaling is essential for initiating DNA replication in lung progenitor cells. Furthermore, MDM2 activates the Notch signaling pathway and expression of EMT markers, indicative of epithelial regeneration. This is the first report to our knowledge demonstrating a direct p53-independent participation of MDM2 in progenitor cell proliferation and epithelial repair after lung injury, distinct from a p53-degrading antiapoptotic effect preventing injury.

Evaluation of jawbone morphology and bone density indices in panoramic radiographs of selective serotonin reuptake inhibitor users: a preliminary study.

OBJECTIVES:: To assess the influence of selective serotonin reuptake inhibitor (SSRI) use on jawbone and bone mineral density by retrospective analysis of panoramic radiographs. METHODS:: Radiographic and clinical records were sourced from the Division of Orthodontics and TMJD, Eastman Institute for Oral Health, University of Rochester. Randomly selected adults (20-65 years) were categorized into: "Active" (with history of SSRI use of >6 months) and a "Control" group. Panoramic indices: Klemetti index (KI), panoramic mandibular index, antegonial notching index, condylar pathology, mandibular cortical width (MCW)⁠ and mean ramus height were recorded. Frequency-weighted Χ2 tests and multinomial regression controlling for age and gender were applied to categorical indices (KI, condylar pathology, antegonial notching index). Multivariate generalized linear modeling was applied to mean ramus height, MCW and panoramic mandibular index. Multiple regression analyses determined: (a) panoramic indices that best predicted SSRI use, and (b) independent predictors of KI category. RESULTS:: 64 SSRI users and 48 Controls were assessed. SSRI users had significantly higher odds of having worse KI status than normal [mildly to moderately eroded cortex: odds ratio (OR) = 2.926, 95% CI (1.07-8.04) and severely eroded cortex: OR = 19.86, 95% CI (3.91-100.69)], more frequent flat condylar anatomy (right side: p = 0.009, left side: p < 0.001) but greater ramus height (p = 0.001) and mandibular cortical width (p = 0.032). Age, gender, SSRI use each significantly impacted KI. Only SSRI use significantly impacted condylar pathology, ramus height and MCW. KI category (OR = 1.3) was the best panoramic predictor of SSRI use. Conversely, KI category C3 was significantly predicted by SSRI use (OR = 31.2, p = 0.002), female gender (17.5, p = 0.006), and severe antegonial notching (OR = 1289, p < 0.001). CONCLUSIONS:: SRRI use was significantly associated with worse panoramic morphometric indices: KI, condylar pathology, ramus height, and MCW, where KI was its strongest predictor. Worse KI was independently predicted by SSRI use.

Target-site mutation accumulation among ALS inhibitor-resistant Palmer amaranth.

BACKGROUND: Palmer amaranth (Amaranthus palmeri S. Wats) is one of the most common and troublesome weeds in the USA. Palmer amaranth resistance to acetolactate synthase (ALS) inhibitors is widespread in the USA, as in Arkansas. The cross-resistance patterns and mechanism of resistance are not known. Experiments were conducted to determine cross-resistance to ALS inhibitors and identify target-site mutations in 20 Palmer amaranth localities from 13 counties in Arkansas. RESULTS: All Palmer amaranth localities tested had plants cross-resistant to imazethapyr, flumetsulam, primisulfuron, pyrithiobac and trifloxysulfuron. The dose of trifloxysulfuron that caused 50% control was 21-56-fold greater for resistant accessions than for susceptible ones. All but three resistant plants analyzed had one or two relative copies of ALS; one plant had seven relative copies. All resistant plants tested (18 localities) carried the Trp574Leu mutation, which is known to confer broad resistance to ALS inhibitors, supporting the cross-resistance pattern observed. Besides the Trp574Leu mutation, 30% of localities had individuals with one additional resistance-conferring mutation including Ala122Thr, Pro197Ala or Ser653Asn. CONCLUSION: The Trp574Leu mutation in ALS is the primary mechanism of resistance to ALS inhibitors in Palmer amaranth from Arkansas, USA. In some localities, multiple mutations have accumulated in one plant. All localities tested contained plants with resistance to five families of ALS inhibitors. Localities with extremely high resistance to ALS inhibitors, and those outside the subset we studied, may harbor non-target site resistance mechanisms. ALS inhibitors are generally no longer effective on Palmer amaranth in these localities from the US mid-south. © 2018 Society of Chemical Industry.

Umbilical Coiling Index Assessment During Routine Fetal Anatomic Survey: A Screening Tool for Fetuses at Risk.

BACKGROUND: The umbilical cord is the lifeline of the foetus as it supplies water, nutrients, and oxygen. Protection of these blood vessels is needed and provided by Wharton's Jelly, amniotic fluid and the helical pattern, or coiling, of the umbilical cord vessels. AIM: To establish the relationship between antenatal umbilical cord coiling index (aUCI) measured at 18-20 weeks along with level II USG and adverse perinatal outcomes. METHODS: A cross-sectional study was conducted on 408 antenatal women, enrolled at the time of fetal anatomic survey, and their cord coiling index (aUCI) was measured, and its association with perinatal outcomes was observed. Umbilical coiling index was classified as Hypocoiled if UCI <10th percentile, hypercoiled >90th percentile, normocoiled between 10th and 90th percentile. RESULTS: 408 antenatal women were enrolled for the study. Mean aUCI was 0.43 ± 0.30 (normocoiled group), 0.18 ± 0.4 (hypocoiled), and 0.53 ± 0.05 (hypercoiled group). The average gestational age at delivery in hypocoiled group was 36.8 ± 2.34 weeks, and it was shorter than 38.3 ± 1.82 weeks of the normocoiled group and 38.9 ± 1.72 weeks of the hypercoiled group. Mean birth weight observed was 2055 ± 744 (hypocoiled group), 3049 ± 564 (hypercoiled), and 3102 ± 564 (normocoiled) p < 0.001. Preterm births 52 (59%) and low birth weight 76 (69%) were significantly associated with hypocoiling. CONCLUSION: Abnormal umbilical cord coiling index, detected at the fetal ultrasound anatomic survey in the second trimester (18-20 weeks), can be used potentially as a screening or as a predictive tool for adverse antenatal or perinatal events.

Mutant p53 establishes targetable tumor dependency by promoting unscheduled replication.

Gain-of-function (GOF) p53 mutations are observed frequently in most intractable human cancers and establish dependency for tumor maintenance and progression. While some of the genes induced by GOF p53 have been implicated in more rapid cell proliferation compared with p53-null cancer cells, the mechanism for dependency of tumor growth on mutant p53 is unknown. This report reveals a therapeutically targetable mechanism for GOF p53 dependency. We have shown that GOF p53 increases DNA replication origin firing, stabilizes replication forks, and promotes micronuclei formation, thus facilitating the proliferation of cells with genomic abnormalities. In contrast, absence or depletion of GOF p53 leads to decreased origin firing and a higher frequency of fork collapse in isogenic cells, explaining their poorer proliferation rate. Following genome-wide analyses utilizing ChIP-Seq and RNA-Seq, GOF p53-induced origin firing, micronuclei formation, and fork protection were traced to the ability of GOF p53 to transactivate cyclin A and CHK1. Highlighting the therapeutic potential of CHK1's role in GOF p53 dependency, experiments in cell culture and mouse xenografts demonstrated that inhibition of CHK1 selectively blocked proliferation of cells and tumors expressing GOF p53. Our data suggest the possibility that checkpoint inhibitors could efficiently and selectively target cancers expressing GOF p53 alleles.

Gain-of-function p53 activates multiple signaling pathways to induce oncogenicity in lung cancer cells.

Gain-of-function (GOF) mutants of p53 upregulate genes implicated in cell proliferation and oncogenesis. Here, we report that GOF p53 induces tumorigenicity through simultaneous activation of key oncogenic pathways including those controlling putative tumor-initiating cell functions. We determined that in cells expressing p53-R273H, GOF p53 simultaneously upregulates genes from multiple signaling pathways by recognizing promoters containing distinct transcription factor (TF) binding sites. Our analytical data support a model in which GOF p53 complexes with two TFs on the promoter-a mediator protein, Med17, and a histone acetyl transferase, activating histone acetylation-and enhances gene expression to signal cell proliferation and oncogenesis. Thus, therapeutic inhibition of one GOF p53-induced pathway would be insufficient to prevent tumor growth as the oncoprotein activates a multitude of parallel pathways. This discovery suggests enormous selection advantage for cancer cells with GOF p53 to induce oncogenic growth, highlighting the problems of cancer therapy.

Impact of volunteer rice infestation on yield and grain quality of rice.

BACKGROUND: Volunteer rice (Oryza sativa L.) grains may differ in physicochemical traits from cultivated rice, which may reduce the quality of harvested rice grain. To evaluate the effect of volunteer rice on cultivated rice, fields were surveyed in Arkansas in 2012. RESULTS: Cropping history that included hybrid cultivars in the previous two years (2010 and 2011) had higher volunteer rice infestation (20%) compared with fields planted previously with inbred rice (5.5%). The total grain yield of rice was reduced by 0.4% for every 1% increase in volunteer rice density. The grain quality did not change in fields planted with the same cultivar for three years. Volunteer rice density of at least 7.6% negatively impacted the head rice and when infestation reached 17.7%, it also reduced the rice grain yield. The protein and amylose contents of rice were not affected until volunteer rice infestation exceeded 30%. CONCLUSION: Crop rotation systems that include hybrid rice are expected to have higher volunteer rice infestation than systems without hybrid rice. It is predicted that, at 8% infestation, volunteer rice will start to impact head rice yield and will reduce total yield at 18% infestation. It could alter the chemical quality of rice grain at >30% infestation. © 2016 Society of Chemical Industry.