CDK9 inhibition inhibits multiple oncogenic transcriptional and epigenetic pathways in prostate cancer.

BACKGROUND: Cyclin-dependent kinase 9 (CDK9) stimulates oncogenic transcriptional pathways in cancer and CDK9 inhibitors have emerged as promising therapeutic candidates. METHODS: The activity of an orally bioavailable CDK9 inhibitor, CDKI-73, was evaluated in prostate cancer cell lines, a xenograft mouse model, and patient-derived tumor explants and organoids. Expression of CDK9 was evaluated in clinical specimens by mining public datasets and immunohistochemistry. Effects of CDKI-73 on prostate cancer cells were determined by cell-based assays, molecular profiling and transcriptomic/epigenomic approaches. RESULTS: CDKI-73 inhibited proliferation and enhanced cell death in diverse in vitro and in vivo models of androgen receptor (AR)-driven and AR-independent models. Mechanistically, CDKI-73-mediated inhibition of RNA polymerase II serine 2 phosphorylation resulted in reduced expression of BCL-2 anti-apoptotic factors and transcriptional defects. Transcriptomic and epigenomic approaches revealed that CDKI-73 suppressed signaling pathways regulated by AR, MYC, and BRD4, key drivers of dysregulated transcription in prostate cancer, and reprogrammed cancer-associated super-enhancers. These latter findings prompted the evaluation of CDKI-73 with the BRD4 inhibitor AZD5153, a combination that was synergistic in patient-derived organoids and in vivo. CONCLUSION: Our work demonstrates that CDK9 inhibition disrupts multiple oncogenic pathways and positions CDKI-73 as a promising therapeutic agent for prostate cancer, particularly aggressive, therapy-resistant subtypes.

Targeting hyaluronan-mediated motility receptor (HMMR) enhances response to androgen receptor signalling inhibitors in prostate cancer.

BACKGROUND: Resistance to androgen receptor signalling inhibitors (ARSIs) represents a major clinical challenge in prostate cancer. We previously demonstrated that the ARSI enzalutamide inhibits only a subset of all AR-regulated genes, and hypothesise that the unaffected gene networks represent potential targets for therapeutic intervention. This study identified the hyaluronan-mediated motility receptor (HMMR) as a survival factor in prostate cancer and investigated its potential as a co-target for overcoming resistance to ARSIs. METHODS: RNA-seq, RT-qPCR and Western Blot were used to evaluate the regulation of HMMR by AR and ARSIs. HMMR inhibition was achieved via siRNA knockdown or pharmacological inhibition using 4-methylumbelliferone (4-MU) in prostate cancer cell lines, a mouse xenograft model and patient-derived explants (PDEs). RESULTS: HMMR was an AR-regulated factor that was unaffected by ARSIs. Genetic (siRNA) or pharmacological (4-MU) inhibition of HMMR significantly suppressed growth and induced apoptosis in hormone-sensitive and enzalutamide-resistant models of prostate cancer. Mechanistically, 4-MU inhibited AR nuclear translocation, AR protein expression and subsequent downstream AR signalling. 4-MU enhanced the growth-suppressive effects of 3 different ARSIs in vitro and, in combination with enzalutamide, restricted proliferation of prostate cancer cells in vivo and in PDEs. CONCLUSION: Co-targeting HMMR and AR represents an effective strategy for improving response to ARSIs.

Characterization of Transferrable Mechanisms of Quinolone Resistance (TMQR) among Quinolone-resistant Escherichia coli and Klebsiella pneumoniae causing Urinary Tract Infection in Nepalese Children.

BACKGROUND: Transferrable mechanisms of quinolone resistance (TMQR) can lead to fluoroquinolone non-susceptibility in addition to chromosomal mechanisms. Some evidence suggests that fluoroquinolone resistance is increasing among the pediatric population. We sought to determine the occurrence of TMQR genes among quinolone-resistant E. coli and K. pneumoniae causing urinary tract infections among Nepalese outpatient children (< 18 years) and identify molecular characteristics of TMQR-harboring isolates. METHODS: We performed antimicrobial susceptibility testing, phenotypic extended-spectrum ß-lactamase (ESBL) and modified carbapenem inactivation method tests, and investigated the presence of six TMQR genes (qnrA, qnrB, qnrS, aac(6')-Ib-cr, oqxAB, qepA), three ESBL genes (blaCTX-M, blaTEM, blaSHV), and five carbapenemase genes (blaNDM, blaOXA-48, blaKPC, blaIMP, blaVIM). The quinolone resistance-determining region (QRDR) of gyrA and parC were sequenced for 35 TMQR-positive isolates. RESULTS: A total of 74/147 (50.3%) isolates were TMQR positive by multiplex PCR [aac(6')-Ib-cr in 48 (32.7%), qnrB in 23 (15.7%), qnrS in 18 (12.3%), qnrA in 1 (0.7%), and oqxAB in 1 (0.7%) isolate]. The median ciprofloxacin minimum inhibitory concentration of TMQR-positive isolates (64 µg/mL) was two-fold higher than those without TMQR (32 µg/mL) (p = 0.004). Ser-83→Leu and Asp-87→Asn in GyrA and Ser-80→Ile in ParC were the most common QRDR mutations (23 of 35). In addition, there was a statistically significant association between TMQR and two ß-lactamase genes; blaCTX-M (p = 0.037) and blaTEM (p = 0.000). CONCLUSION: This study suggests a high prevalence of TMQR among the quinolone-resistant E. coli and K. pneumoniae isolates causing urinary tract infection in children in this area of Nepal and an association with the carriage of ESBL gene. This is a challenge for the management of urinary infections in children. Comprehensive prospective surveillance of antimicrobial resistance in these common pathogens will be necessary to devise strategies to mitigate the emergence of further resistance.

Nitrous Oxide Fluxes in Fertilized L. Plantations across a Gradient of Soil Drainage Classes.

The effect of fertilizer management on nitrous oxide (NO) fluxes in agricultural ecosystems is well documented; however, our knowledge of these effects in managed forests is minimal. We established a comprehensive research study to address this knowledge gap across a range of soil drainage classes (poorly, moderately, and well drained) common in southern pine plantation management. Fertilizer treatments in each drainage class comprised of control (no fertilizer), urea + phosphorus (P), and P-coated urea fertilizer (CUF). Fertilization (168 kg N ha) occurred independently during the spring, summer, and fall to assess the effects of application timing. Nitrous oxide sampling, using vented static chambers, started immediately after seasonal fertilizer application and was performed every 6 wk for more than 1 yr. Time-integrated net annual NO emissions increased with urea (1.15 kg NO-N ha) and CUF (0.88 kg NO-N ha) application compared with unfertilized control (0.22 kg NO-N ha). Mean annual NO flux was significantly increased with fall fertilization (1.17 kg NO-N ha) relative to spring (0.73 kg NO-N ha) or summer (0.33 kg NO-N ha). Similarly, average annual NO flux was higher in poorly drained soils (1.40 kg NO-N ha) than in moderately drained (0.46 kg NO-N ha) and well-drained soils (0.39 kg NO-N ha). This study suggests that NO emissions after fertilization can be minimized by avoiding fall fertilization and poorly drained soils and by selecting enhanced-efficiency N fertilizers over urea.

Local delivery of linezolid in the treatment of complex orthopedic bone and joint infections in patients with vancomycin allergy: a case series.

Introduction: Osteomyelitis is a challenging bone infection associated with ischemia, trauma, or various surgical procedures (e.g., joint reconstruction). Treatment involves eradicating infected bone and soft tissue, local antibiotic delivery, and a 6-week course of antibiotics. Methicillin-resistant Staphylococcus aureus (MRSA) infections are common, and vancomycin is the standard treatment, but alternatives like linezolid are needed in vancomycin-resistant and vancomycin-allergic patients. Methods: A retrospective chart review was conducted on patients treated by the senior author between 2013 and 2021. The study included patients who received local delivery of linezolid for bone and/or joint infection with documented evidence of vancomycin allergy. Patient demographics, surgical details, linezolid delivery method, and outcomes were recorded. Clinical outcomes and subsequent procedures leading to infection eradication were documented. Results: A total of 13 patients were treated with linezolid-antibiotic-laden spacers with polymethyl methacrylate (PMMA) carrier. Nine patients were successfully treated using limb-salvage techniques and were still infection-free after a mean follow-up of 55.5 months. Conclusions: Linezolid-loaded bone cement is an option for managing chronic bone and joint infections, particularly MRSA, in patients with vancomycin allergy.

The overlap of accessory virulence factors and multidrug resistance among clinical and surveillance Klebsiella pneumoniae isolates from a neonatal intensive care unit in Nepal: a single-centre experience in a resource-limited setting.

BACKGROUND: There is a lack of data on the characteristics of overlap between acquired antimicrobial resistance and virulence factors in Klebsiella pneumoniae in high-risk settings, especially with the inclusion of surveillance isolates along with the clinical. We investigated K. pneumoniae isolates, from a neonatal intensive care unit (NICU) in Nepal, for the presence of both accessory virulence factors and acquired antimicrobial resistance. METHODS: Thirty-eight clinical and nineteen surveillance K. pneumoniae isolates obtained between January 2017 and August 2022 in the NICU of Siddhi Memorial Hospital, Bhaktapur, Nepal were investigated with antimicrobial susceptibility testing, PCR-based detection of ß-lactamases and virulence factors, and genetic similarity by ERIC-PCR. RESULTS: K. pneumoniae was found positive in 37/85 (43.5%) blood culture-positive neonatal bloodstream infections, 34/954 (3.6%) patient surveillance cultures, and 15/451 (3.3%) environmental surveillance samples. Among 57 isolates analyzed in this study, we detected multidrug resistance in 37/57 (64.9%), which was combined with at least one accessory virulence factor in 21/37 (56.8%). This overlap was mostly among ß-lactamase producing isolates with accessory mechanisms of iron acquisition. These isolates displayed heterogenous ERIC-PCR patterns suggesting genetic diversity. CONCLUSIONS: The clinical significance of this overlap between acquired antimicrobial resistance and accessory virulence genes in K. pneumoniae needs further investigation. Better resource allocation is necessary to strengthen infection prevention and control interventions in resource-limited settings.

The causes of bacterial bloodstream infections and antimicrobial resistance patterns in children attending a secondary care hospital in Bhaktapur, Nepal, 2017-2022: a retrospective study.

Objectives: Data on antimicrobial resistance (AMR) among children in Nepal are limited. Here we have characterized the causes of bacterial bloodstream infections (BSIs), antimicrobial resistance patterns and the mechanisms of ß-lactamase production in Enterobacterales among children attending outpatient and inpatient departments of a secondary care paediatric hospital in Nepal. Methods: We retrospectively collected demographic and clinical data of culture-proven bacterial BSIs between January 2017 and December 2022 among children <18 years attending a 50-bedded paediatric hospital. Stored isolates were subcultured for antimicrobial susceptibility testing against commonly used antimicrobials. Enterobacterales displaying non-susceptibility to ß-lactams were phenotypically and genotypically investigated for ESBLs, plasmid-mediated AmpC (pAmpC) ß-lactamases and carbapenemases. Results: A total of 377 significant bacteria were isolated from 27 366 blood cultures. Among 91 neonates with a BSI, Klebsiella pneumoniae (n = 39, 42.4%), Pseudomonas aeruginosa (n = 15, 16.3%) and Acinetobacter baumannii complex (n = 13, 14.1%) were most common. In the non-neonates, 275/285 (96.5%) infections were community-acquired including Staphylococcus aureus (n = 89, 32.4%), Salmonella Typhi (n = 54, 19.6%) and Streptococcus pneumoniae (n = 32, 11.6%). Among the 98 S. aureus, 29 (29.6%) were methicillin-resistant Staphylococcus aureus. K. pneumoniae and Escherichia coli demonstrated non-susceptibility to extended-spectrum cephalosporins and carbapenems in both community and hospital-acquired cases. For E. coli and K. pneumoniae, blaCTX-M (45/46), blaEBC (7/10) and blaOXA-48 (5/6) were common among their respective groups. Conclusions: We determined significant levels of AMR among children attending a secondary care paediatric hospital with BSI in Nepal. Nationwide surveillance and implementation of antimicrobial stewardship policies are needed to combat the challenge imposed by AMR.

ACSM1 and ACSM3 Regulate Fatty Acid Metabolism to Support Prostate Cancer Growth and Constrain Ferroptosis.

Solid tumors are highly reliant on lipids for energy, growth, and survival. In prostate cancer, the activity of the androgen receptor (AR) is associated with reprogramming of lipid metabolic processes. Here, we identified acyl-CoA synthetase medium chain family members 1 and 3 (ACSM1 and ACSM3) as AR-regulated mediators of prostate cancer metabolism and growth. ACSM1 and ACSM3 were upregulated in prostate tumors compared with nonmalignant tissues and other cancer types. Both enzymes enhanced proliferation and protected prostate cancer cells from death in vitro, whereas silencing ACSM3 led to reduced tumor growth in an orthotopic xenograft model. ACSM1 and ACSM3 were major regulators of the prostate cancer lipidome and enhanced energy production via fatty acid oxidation. Metabolic dysregulation caused by loss of ACSM1/3 led to mitochondrial oxidative stress, lipid peroxidation, and cell death by ferroptosis. Conversely, elevated ACSM1/3 activity enabled prostate cancer cells to survive toxic levels of medium chain fatty acids and promoted resistance to ferroptosis-inducing drugs and AR antagonists. Collectively, this study reveals a tumor-promoting function of medium chain acyl-CoA synthetases and positions ACSM1 and ACSM3 as key players in prostate cancer progression and therapy resistance. Significance: Androgen receptor-induced ACSM1 and ACSM3 mediate a metabolic pathway in prostate cancer that enables the utilization of medium chain fatty acids for energy production, blocks ferroptosis, and drives resistance to clinically approved antiandrogens.

Biochar as a negative emission technology: A synthesis of field research on greenhouse gas emissions.

Biochar is one of the few nature-based technologies with potential to help achieve net-zero emissions agriculture. Such an outcome would involve the mitigation of greenhouse gas (GHG) emission from agroecosystems and optimization of soil organic carbon sequestration. Interest in biochar application is heightened by its several co-benefits. Several reviews summarized past investigations on biochar, but these reviews mostly included laboratory, greenhouse, and mesocosm experiments. A synthesis of field studies is lacking, especially from a climate change mitigation standpoint. Our objectives are to (1) synthesize advances in field-based studies that have examined the GHG mitigation capacity of soil application of biochar and (2) identify limitations of the technology and research priorities. Field studies, published before 2022, were reviewed. Biochar has variable effects on GHG emissions, ranging from decrease, increase, to no change. Across studies, biochar reduced emissions of nitrous oxide (N2 O) by 18% and methane (CH4 ) by 3% but increased carbon dioxide (CO2 ) by 1.9%. When biochar was combined with N-fertilizer, it reduced CO2 , CH4 , and N2 O emissions in 61%, 64%, and 84% of the observations, and biochar plus other amendments reduced emissions in 78%, 92%, and 85% of the observations, respectively. Biochar has shown potential to reduce GHG emissions from soils, but long-term studies are needed to address discrepancies in emissions and identify best practices (rate, depth, and frequency) of biochar application to agricultural soils.

Characteristics of Pregnant Women and Risk Factors of Their Newborn for Admission to a Neonatal Intensive Care Unit in Nepal.

BACKGROUND: Nepal has progressed gradually in reducing under-5 mortality and neonatal mortality; however, they are still high at 30.8 and 19.8 per 1000 live births, respectively. Neonatal mortality constituted about 64% of the under-5 mortality in 2019, higher than the global average of 47%. METHODS: This is a prospective study among pregnant women and their newborn babies in Siddhi Memorial Hospital, Bhaktapur, Nepal, from October 2017 to April 2018. Demographic and clinical data, high vaginal swabs of pregnant mothers, and umbilical cord blood were collected. High vaginal swabs were cultured, and umbilical cord blood samples were cultured and tested for inflammatory markers. After discharge to home, neonates were followed for 28 days of life by weekly phone calls. RESULTS: Total number of pregnant mothers enrolled was 151. The median age was 26 years (IQR: 18-40), and the proportion of adolescent mothers was 4.7%. Half of the deliveries were done by the caesarian section, and 8.6% had gestational age <37 weeks. High vaginal swab cultures were positive in 8.2% of the samples (n=135), and Escherichia coli was the most common bacteria. Out of 153 newborn babies (2 were twins), 8 (5.2%) were admitted to the neonatal intensive care unit. The proportion of low birth weight was 13%, and it was independently associated with neonatal intensive care unit admission (adjusted OR=9.4, 95%CI 1.8-50.1; P value= 0.009). CONCLUSIONS: Adolescent pregnancies and Low Birth Weight babies were commonly observed. Both of these issues need to be addressed by effective measures that would improve the current situation of maternal and child health in Nepal.

Potent Stimulation of the Androgen Receptor Instigates a Viral Mimicry Response in Prostate Cancer.

Inhibiting the androgen receptor (AR), a ligand-activated transcription factor, with androgen deprivation therapy is a standard-of-care treatment for metastatic prostate cancer. Paradoxically, activation of AR can also inhibit the growth of prostate cancer in some patients and experimental systems, but the mechanisms underlying this phenomenon are poorly understood. This study exploited a potent synthetic androgen, methyltestosterone (MeT), to investigate AR agonist-induced growth inhibition. MeT strongly inhibited growth of prostate cancer cells expressing AR, but not AR-negative models. Genes and pathways regulated by MeT were highly analogous to those regulated by DHT, although MeT induced a quantitatively greater androgenic response in prostate cancer cells. MeT potently downregulated DNA methyltransferases, leading to global DNA hypomethylation. These epigenomic changes were associated with dysregulation of transposable element expression, including upregulation of endogenous retrovirus (ERV) transcripts after sustained MeT treatment. Increased ERV expression led to accumulation of double-stranded RNA and a "viral mimicry" response characterized by activation of IFN signaling, upregulation of MHC class I molecules, and enhanced recognition of murine prostate cancer cells by CD8+ T cells. Positive associations between AR activity and ERVs/antiviral pathways were evident in patient transcriptomic data, supporting the clinical relevance of our findings. Collectively, our study reveals that the potent androgen MeT can increase the immunogenicity of prostate cancer cells via a viral mimicry response, a finding that has potential implications for the development of strategies to sensitize this cancer type to immunotherapies. Significance: Our study demonstrates that potent androgen stimulation of prostate cancer cells can elicit a viral mimicry response, resulting in enhanced IFN signaling. This finding may have implications for the development of strategies to sensitize prostate cancer to immunotherapies.

Emergence of Multi-Drug Resistance and Its Association With Uncommon Serotypes of Streptococcus agalactiae Isolated From Non-neonatal Patients in Thailand.

Group B streptococcus (GBS) or Streptococcus agalactiae is an opportunistic pathogen that causes serious illness in newborns, pregnant women, and adults. However, insufficient detection methods and disease prevention programs have contributed to an increase in the incidence and fatality rates associated with this pathogen in non-neonatal patients. This study aimed to investigate factors of the observed increased incidence by investigation of serotype distribution, virulence factors, and antimicrobial susceptibility patterns from invasive GBS disease among non-neonatal patients in Thailand. During 2017-2018, a total of 109 S. agalactiae isolates were collected from non-pregnant patients. There were 62 males and 47 females, with an average age of 63.5 years (range: 20 - 96). Serotypes were determined by latex agglutination assay and multiplex polymerase chain reaction (PCR)-based assay. Among those isolates, seven virulence genes (rib, bca, pavA, lmb, scpB, cylE, and cfb) were detected by PCR amplification, and were determined for their susceptibility to 20 antimicrobial agents using a SensititreTM Streptococcus species STP6F AST plate. Among the study isolates, serotype III was predominant (52.3%), followed by serotype V and serotype VI (13.8% for each), serotype Ib (11.9%), and other serotypes (8.2%). Of the seven virulence genes, pavA was found in 67.0%. Except for one, there were no significant differences in virulence genes between serotype III and non-serotype III. Study isolates showed an overall rate of non-susceptibility to penicillin, the first-line antibiotic, of only 0.9%, whereas the resistance rates measured in tetracycline, clindamycin, azithromycin, and erythromycin were 41.3, 22.0, 22.0, and 22.0%, respectively. Strains that were resistant to all four of those drugs were significantly associated with non-serotype III (p < 0.001). Using multi-locus sequence typing (MLST), 40.0% of the four-drug-resistant isolates belonged to serotype VI/ST1, followed by serotype Ib/ST1 (35.0%). Cluster analysis with global GBS isolates suggested that the multiple drug-resistant isolates to be strongly associated with the clonal complex (CC) 1 (p < 0.001). Compared to the 2014 study of 210 invasive GBS isolates conducted in 12 tertiary hospitals in Thailand, the proportion of serotype III has dramatically dropped from nearly 90% to about 50%. This suggests that resistances to the second-line antibiotics for GBS might be the selective pressure causing the high prevalence of non-serotype III isolates.

A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth.

Alterations to the androgen receptor (AR) signalling axis and cellular metabolism are hallmarks of prostate cancer. This study provides insight into both hallmarks by uncovering a novel link between AR and the pentose phosphate pathway (PPP). Specifically, we identify 6-phosphogluoconate dehydrogenase (6PGD) as an androgen-regulated gene that is upregulated in prostate cancer. AR increased the expression of 6PGD indirectly via activation of sterol regulatory element binding protein 1 (SREBP1). Accordingly, loss of 6PGD, AR or SREBP1 resulted in suppression of PPP activity as revealed by 1,2-13C2 glucose metabolic flux analysis. Knockdown of 6PGD also impaired growth and elicited death of prostate cancer cells, at least in part due to increased oxidative stress. We investigated the therapeutic potential of targeting 6PGD using two specific inhibitors, physcion and S3, and observed substantial anti-cancer activity in multiple models of prostate cancer, including aggressive, therapy-resistant models of castration-resistant disease as well as prospectively collected patient-derived tumour explants. Targeting of 6PGD was associated with two important tumour-suppressive mechanisms: first, increased activity of the AMP-activated protein kinase (AMPK), which repressed anabolic growth-promoting pathways regulated by acetyl-CoA carboxylase 1 (ACC1) and mammalian target of rapamycin complex 1 (mTORC1); and second, enhanced AR ubiquitylation, associated with a reduction in AR protein levels and activity. Supporting the biological relevance of positive feedback between AR and 6PGD, pharmacological co-targeting of both factors was more effective in suppressing the growth of prostate cancer cells than single-agent therapies. Collectively, this work provides new insight into the dysregulated metabolism of prostate cancer and provides impetus for further investigation of co-targeting AR and the PPP as a novel therapeutic strategy.

Correction to: Changes in nutritional status of children who lived in temporary shelters in Bhaktapur municipality after the 2015 Nepal earthquake.

[This corrects the article DOI: 10.1186/s41182-020-00225-8.].

Changes in nutritional status of children who lived in temporary shelters in Bhaktapur municipality after the 2015 Nepal earthquake.

BACKGROUND: The nutritional status of children may deteriorate after natural disasters such as earthquakes. A 7.8 Richter scale earthquake struck Nepal in 2015 that affected 1.1 million children. Children whose homes were destroyed and had to live in temporary shelters were at risk of malnutrition. With the support of Nagasaki University School of Tropical Medicine and Global Health (TMGH) and Siddhi Memorial Hospital (SMH), we conducted a nutritional survey of under-5 children living in temporary shelters in Bhaktapur Municipality in 2015 immediately after the earthquake and a follow-up survey in 2017. RESULTS: We found 591 under-5 children living in 22 temporary shelters in 2015. A total of 285 children were followed up and re-assessed in 2017. In a paired analysis (n = 285), the prevalence of underweight children increased from 10.9% in 2015 to 14.0% in 2017 (P < 0.001), stunting increased from 26.7 to 31.9% (P = 0.07), and wasting decreased from 4.2 to 2.5% (P = 0.19). CONCLUSIONS: Children who lived in temporary shelters after the 2015 Nepal earthquake might be at increased risk of a deterioration in nutritional status.

Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis.

Fatty acid ß-oxidation (FAO) is the main bioenergetic pathway in human prostate cancer (PCa) and a promising novel therapeutic vulnerability. Here we demonstrate therapeutic efficacy of targeting FAO in clinical prostate tumors cultured ex vivo, and identify DECR1, encoding the rate-limiting enzyme for oxidation of polyunsaturated fatty acids (PUFAs), as robustly overexpressed in PCa tissues and associated with shorter relapse-free survival. DECR1 is a negatively-regulated androgen receptor (AR) target gene and, therefore, may promote PCa cell survival and resistance to AR targeting therapeutics. DECR1 knockdown selectively inhibited ß-oxidation of PUFAs, inhibited proliferation and migration of PCa cells, including treatment resistant lines, and suppressed tumor cell proliferation and metastasis in mouse xenograft models. Mechanistically, targeting of DECR1 caused cellular accumulation of PUFAs, enhanced mitochondrial oxidative stress and lipid peroxidation, and induced ferroptosis. These findings implicate PUFA oxidation via DECR1 as an unexplored facet of FAO that promotes survival of PCa cells.

Greenhouse gas emissions and global warming potential of reclaimed forest and grassland soils.

Although greenhouse gas (GHG) emissions from soils are important, reclaimed mine soil (RMS) ecosystems are not widely assessed. Postreclamation land uses (forest, hay, and pasture) were investigated to: (i) monitor the magnitude of GHG fluxes, (ii) estimate their global warming potential (GWP), (iii) identify the relationship between GHG fluxes and soil properties, and (iv) develop a soil quality index by principal component analysis (PCA). The GHG fluxes were measured for 1 yr cycle and simultaneous measurements were also made for soil moisture and temperature. The RMS-forest, -hay, and -pasture land uses had weighted average fluxes of 1.16, 1.66, and 3.06 g CO(2)-C m(-2) d(-1); 0.33, 0.48 and 1.1 mg CH(4)-C m(-2) d(-1); and 0.33, 0.70, and 1.06 mg N(2)O-N m(-2) d(-1), respectively. The CO(2), CH(4), and N(2)O fluxes were consistently high in the RMS-pasture and low in the RMS-forest. The GWP (CO(2)-C equivalent) of the postreclamation land uses was in the order of RMS-forest (4.5 Mg ha(-1) yr(-1)) = RMS-hay (6.8 Mg ha(-1) yr(-1)) < RMS-pasture (12.3 Mg ha(-1) yr(-1)). The PCA showed that four PCs with eigenvalues > 1 explained 88.8% of the total variance in the soil properties. The first PC is mostly characterized by soil physical properties and the second by chemical properties. Soil and air temperatures were positively correlated with CO(2), CH(4), and N(2)O fluxes. The results suggest that GWP from RMS can be minimized by establishing forest land use.

Prevalence of vitamin D deficiency in pregnant women and their babies in Bhaktapur, Nepal.

BACKGROUND: Vitamin D deficiency has been observed worldwide in pregnant women and their newborns. Maternal vitamin D deficiency can lead to deficiency in their newborn baby and has been linked with various complications during pregnancy and delivery. There is risk of premature delivery and it is associated with high neonatal mortality. METHODS: Seventy-nine pregnant women who were admitted to the Siddhi Memorial Hospital for delivery and their newborn babies were enrolled in the study. Maternal blood samples were taken before delivery while umbilical cord blood samples of their babies were taken after delivery. Serum vitamin D level and calcium level were assessed by fluorescence immunoassay using Ichromax vitamin D kit and endpoint method, respectively in the Siddhi Memorial Hospital laboratory. RESULTS: Mean +/- SD serum vitamin D and calcium levels in pregnant mother before delivery were 14.6 +/- 8.5 ng/ml and 8.0 +/- 0.5 mg/dl, respectively, and in the cord blood were 25.7 +/- 11.2 ng/ml and 8.6 +/- 0.9 mg/dl, respectively. Eighty-one percent of the mothers and 35.8% of their babies were found to have vitamin D deficiency. Although 97.5% of the pregnant women were taking calcium supplementation, serum calcium was found lower than the normal reference value in 67% of the pregnant women and 64.2% of their babies. There were a linear relationship between the maternal and baby's serum vitamin D (P < 0.001) and calcium (P < 0.001) levels. CONCLUSION: There is high prevalence of vitamin D and calcium deficiency in pregnant mothers and newborn babies in Bhaktapur, Nepal. Pregnant women need to be supplemented with adequate amounts of these nutrients.

Soil carbon and nitrogen in 28-year-old land uses in reclaimed coal mine soils of Ohio.

Carbon (C) and nitrogen (N) play an important role in the restoration of ecosystem functions of reclaimed mine soils (RMSs). Postreclamation land use in RMSs affects soil C and N pools and fluxes. We compared the effects of 28-yr-old postreclamation land uses (forest, hay, and pasture) on selected chemical properties of soil, and C and N pools in reference to undisturbed forest and moderately disturbed agricultural land use in southeastern Ohio. The electrical conductivity was higher in RMSs under hay than that in pasture and forest land uses. The RMSs under pasture, hay, and forest had moderately acidic, neutral to slightly alkaline, and slightly alkaline pH, respectively. In the 0- to 5-cm soil depth, soil organic C (SOC) was higher in RMSs under pasture by 99% and under hay by 52% over that under forest. Similarly, total nitrogen (TN) was higher in RMSs under pasture by 98% and under hay by 43% over that under forest. Aggregate-associated SOC concentration in the 0- to 5-cm depth decreased in the order of RMSs under hay > RMSs under pasture > RMSs under forest. The SOC pools in the 0- to 30-cm depth decreased in the order of RMSs under hay = RMSs under pasture > RMSs under forest = undisturbed forest = agriculture land use. Nitrogen pools followed a similar trend. Hay land use has a better potential for improving soil quality in RMSs by enhancing chemical properties and SOC and TN pools than forest or pasture land uses.