Soil is the most complicated biomaterial on the planet. As with any material, the physical habitat is of prime importance in determining and regulating biological activity. However, until recently ...the opaque nature of soil has meant that any interrogation of its interior architecture has been relatively rudimentary, restricted to simple qualitative expressions of the physical heterogeneity that fail to relate to any specific function. However, new techniques and insights into the biophysical and biochemical processes of this inner space are leading to the developments of theoretical frameworks and experimental approaches that will allow us to sustainably manage Earth's most important resource. We introduce the concept that the soil-microbe system is self-organized and suggest new priorities for research based on an integrative approach that combines biochemistry and biophysics.
It has been shown that sunlit snow and ice plays an important role in processing atmospheric species. Photochemical production of a variety of chemicals has recently been reported to occur in ...snow/ice and the release of these photochemically generated species may significantly impact the chemistry of the overlying atmosphere. Nitrogen oxide and oxidant precursor fluxes have been measured in a number of snow covered environments, where in some cases the emissions significantly impact the overlying boundary layer. For example, photochemical ozone production (such as that occurring in polluted mid-latitudes) of 3–4 ppbv/day has been observed at South Pole, due to high OH and NO levels present in a relatively shallow boundary layer. Field and laboratory experiments have determined that the origin of the observed NOx flux is the photochemistry of nitrate within the snowpack, however some details of the mechanism have not yet been elucidated. A variety of low molecular weight organic compounds have been shown to be emitted from sunlit snowpacks, the source of which has been proposed to be either direct or indirect photo-oxidation of natural organic materials present in the snow. Although myriad studies have observed active processing of species within irradiated snowpacks, the fundamental chemistry occurring remains poorly understood. Here we consider the nature of snow at a fundamental, physical level; photochemical processes within snow and the caveats needed for comparison to atmospheric photochemistry; our current understanding of nitrogen, oxidant, halogen and organic photochemistry within snow; the current limitations faced by the field and implications for the future.
Medulloblastoma (MB) is a highly malignant brain tumor that occurs primarily in children. Although surgery, radiation and high-dose chemotherapy have led to increased survival, many MB patients still ...die from their disease, and patients who survive suffer severe long-term side effects as a consequence of treatment. Thus, more effective and less toxic therapies for MB are critically important. Development of such therapies depends in part on identification of genes that are necessary for growth and survival of tumor cells. Survivin is an inhibitor of apoptosis protein that regulates cell cycle progression and resistance to apoptosis, is frequently expressed in human MB and when expressed at high levels predicts poor clinical outcome. Therefore, we hypothesized that Survivin may have a critical role in growth and survival of MB cells and that targeting it may enhance MB therapy. Here we show that Survivin is overexpressed in tumors from patched (Ptch) mutant mice, a model of Sonic hedgehog (SHH)-driven MB. Genetic deletion of survivin in Ptch mutant tumor cells significantly inhibits proliferation and causes cell cycle arrest. Treatment with small-molecule antagonists of Survivin impairs proliferation and survival of both murine and human MB cells. Finally, Survivin antagonists impede growth of MB cells in vivo. These studies highlight the importance of Survivin in SHH-driven MB, and suggest that it may represent a novel therapeutic target in patients with this disease.
Almost 3000 men who received a placebo in the Prostate Cancer Prevention Trial and who never had a prostate-specific antigen (PSA) level of more than 4.0 ng per milliliter during the seven years of ...the trial underwent a prostate biopsy at the end of the study. Biopsy revealed prostate cancer in 449 men (15 percent), 67 of whom had high-grade tumors.
A PSA level of 4.0 ng per milliliter or less does not rule out the presence of prostate cancer, including high-grade tumors.
When first described in 1979, prostate-specific antigen (PSA) was considered a useful marker for assessing treatment responses and follow-up among patients with prostate cancer.
1
After the publication of reports on several series in which the need for a biopsy of the prostate was based on the results of PSA tests, the potential of the PSA level as a screening tool was recognized.
2
,
3
Further experience led to the consensus that a PSA level of more than 4.0 ng per milliliter had predictive value for the diagnosis of prostate cancer.
4
Disease detection subsequently increased dramatically.
5
More recent data suggest that a . . .
The burden of meningitis in low-and-middle-income countries remains significant, but the infectious causes remain largely unknown, impeding institution of evidence-based treatment and prevention ...decisions. We conducted a validation and application study of unbiased metagenomic next-generation sequencing (mNGS) to elucidate etiologies of meningitis in Bangladesh. This RNA mNGS study was performed on cerebrospinal fluid (CSF) specimens from patients admitted in the largest pediatric hospital, a World Health Organization sentinel site, with known neurologic infections (
= 36), with idiopathic meningitis (
= 25), and with no infection (
= 30), and six environmental samples, collected between 2012 and 2018. We used the IDseq bioinformatics pipeline and machine learning to identify potentially pathogenic microbes, which we then confirmed orthogonally and followed up through phone/home visits. In samples with known etiology and without infections, there was 83% concordance between mNGS and conventional testing. In idiopathic cases, mNGS identified a potential bacterial or viral etiology in 40%. There were three instances of neuroinvasive Chikungunya virus (CHIKV), whose genomes were >99% identical to each other and to a Bangladeshi strain only previously recognized to cause febrile illness in 2017. CHIKV-specific qPCR of all remaining stored CSF samples from children who presented with idiopathic meningitis in 2017 (
= 472) revealed 17 additional CHIKV meningitis cases, exposing an unrecognized meningitis outbreak. Orthogonal molecular confirmation, case-based clinical data, and patient follow-up substantiated the findings. Case-control CSF mNGS surveys can complement conventional diagnostic methods to identify etiologies of meningitis, conduct surveillance, and predict outbreaks. The improved patient- and population-level data can inform evidence-based policy decisions.
Globally, there are an estimated 10.6 million cases of meningitis and 288,000 deaths every year, with the vast majority occurring in low- and middle-income countries. In addition, many survivors suffer from long-term neurological sequelae. Most laboratories assay only for common bacterial etiologies using culture and directed PCR, and the majority of meningitis cases lack microbiological diagnoses, impeding institution of evidence-based treatment and prevention strategies. We report here the results of a validation and application study of using unbiased metagenomic sequencing to determine etiologies of idiopathic (of unknown cause) cases. This included CSF from patients with known neurologic infections, with idiopathic meningitis, and without infection admitted in the largest children's hospital of Bangladesh and environmental samples. Using mNGS and machine learning, we identified and confirmed an etiology (viral or bacterial) in 40% of idiopathic cases. We detected three instances of Chikungunya virus (CHIKV) that were >99% identical to each other and to a strain previously recognized to cause systemic illness only in 2017. CHIKV qPCR of all remaining stored 472 CSF samples from children who presented with idiopathic meningitis in 2017 at the same hospital uncovered an unrecognized CHIKV meningitis outbreak. CSF mNGS can complement conventional diagnostic methods to identify etiologies of meningitis, and the improved patient- and population-level data can inform better policy decisions.
Background The Prostate Cancer Prevention Trial (PCPT) reported a decreased incidence of prostate cancer overall but an increase in the incidence of high-grade prostate cancer with finasteride ...compared with placebo. We assessed whether the increased high-grade prostate cancer associated with finasteride in the PCPT was due to finasteride's potential effects on tumor morphology or prostate size. Methods Prostate biopsies with Gleason score 8–10 (n = 90, finasteride; n = 52, placebo) were examined histologically for hormonal effects, and those with Gleason score 7–10 (n = 282, finasteride; n = 244, placebo) were examined for pathologic surrogates of disease extent. Prostate volumes were measured at biopsy. Samples from radical prostatectomies (n = 222, finasteride; n = 306, placebo) were examined for tumor grade and extent, and, where possible, grades at biopsy and prostatectomy were compared between the groups. Logistic regression was used to analyze differences between treatment groups with respect to pathologic criteria. All statistical tests were two-sided. Results Degenerative hormonal changes in high-grade biopsies were equivalent between the finasteride and placebo groups, but prostate volumes were lower in the finasteride group (median = 25.1 versus 34.4 cm3, P<.001). Pathologic surrogates for tumor extent were lower with finasteride than with placebo, including mean percentage of positive cores (34% versus 38%, P = .016), mean tumor linear extent (greatest 4.4 versus 4.8 mm, P = .19 and aggregate 7.6 versus 9.2 mm, P = .13), bilaterality (22.8% versus 30.6%, P = .046), and perineural invasion (14.2% versus 20.3%, P = .07). Among patients who had prostatectomy, the finasteride-associated increase in high-grade disease (Gleason score ≥ 7) at biopsy (42.7% finasteride versus 25.4% placebo, P<.001) was diminished at prostatectomy (46.4% finasteride versus 38.6% placebo, P = .10). Biopsy identified a greater proportion of patients with high-grade disease present at prostatectomy in the finasteride group than in the placebo group (69.7% versus 50.5%, P = .01). The rate of upgrading (from low-grade cancer at biopsy to high-grade cancer at prostatectomy) and pathologic stage at prostatectomy were similar in both groups. Conclusions Effects of finasteride on prostate volume and selective inhibition of low-grade cancer, rather than effects on tumor morphology, may have contributed to the increase in high-grade cancers with finasteride in the PCPT. Although induction of high-grade cancer cannot be excluded, the results suggest that high-grade cancer was detected earlier and was less extensive in the finasteride group than in the placebo group.
Adenocarcinoma of the prostate is the most commonly diagnosed malignant neoplasm in the United States.
1
Presently, there is no curative treatment for patients with metastatic prostate cancer, who ...have a progressive and eventually fatal clinical course. The median survival of cohorts of patients with metastatic disease who have entered large-scale, prospective, randomized trials during the past three decades has been relatively stable (range, 24 to 36 months).
2
–
6
Initially, the growth of prostate cancer requires androgens. This is the rationale for endocrine manipulations that rely on the suppression of testosterone production to control androgen-dependent tumor growth.
2
–
6
Androgen deprivation has . . .
Very little is known about the spatial organization of soil microbes across scales that are relevant both to microbial function and to field-based processes. The spatial distributions of microbes and ...microbially mediated activity have a high intrinsic variability. This can present problems when trying to quantify the effects of disturbance, management practices, or climate change on soil microbial systems and attendant function. A spatial sampling regime was implemented in an arable field. Cores of undisturbed soil were sampled from a 3 × 3 × 0.9 m volume of soil (topsoil and subsoil) and a biological thin section, in which the in situ distribution of bacteria could be quantified, prepared from each core. Geostatistical analysis was used to quantify the nature of spatial structure from micrometers to meters and spatial point pattern analysis to test for deviations from complete spatial randomness of mapped bacteria. Spatial structure in the topsoil was only found at the microscale (micrometers), whereas evidence for nested scales of spatial structure was found in the subsoil (at the microscale, and at the centimeter to meter scale). Geostatistical ranges of spatial structure at the micro scale were greater in the topsoil and tended to decrease with depth in the subsoil. Evidence for spatial aggregation in bacteria was stronger in the topsoil and also decreased with depth in the subsoil, though extremely high degrees of aggregation were found at very short distances in the deep subsoil. The data suggest that factors that regulate the distribution of bacteria in the subsoil operate at two scales, in contrast to one scale in the topsoil, and that bacterial patches are larger and more prevalent in the topsoil.
In a handful of fertile soil there are billions of microorganisms and yet, even with a conservative estimate, the surface area covered by these organisms is considerably less than 1%. What does this ...tell us about the function of the physical structure in which soil organisms reside and function, collecting, and separating micropopulations from each other and from resources? It would seem that most of the soil is akin to desert regions with little life been supported on its terrains, yet with vast communities of individuals, from an amazing array of species, supported in small-scale habitats, connected or disconnected by saturated or unsaturated pore space over relatively short time-scales. The biodiversity of these communities remains impressive yet overall functionally illusive, bar some considerations of inbuilt redundancy. What is far more impressive is the range of habitats on offer to populations with short-term evolutionary time frames. The availability of spatially and temporally diverse habitats probably gives rise to the biodiversity that we see in soil. It is not too far fetched to state that the majority of habitats on Earth (and indeed extraterrestrial) are revealed in that handful of soil. The key question is what is the functional consequence of such habitat heterogeneity? To answer this it is clear that we need to bring together a new discipline that combines the biology and physics of the soil ecosystem. This biophysical approach, combined, where required, with important mineral-microbe knowledge is needed to help us understand the mechanisms by which soils remain productive, and to identify the tipping-points at which there may be no return to sustainability. This review aims to highlight the importance of addressing the soil ecosystem as a dynamic heterogeneous system focusing on microbiota-habitat interactions. PUBLICATION ABSTRACT\.
In the last 10 years, some regulatory authorities have consistently suggested that the design of randomized controlled trials testing treatments for cachexia should be aimed at demonstrating ...appropriate risk versus benefit, where benefit is defined as concomitant improvement in skeletal muscle mass (or lean mass) and relevant/meaningful physical function or improved survival. ...unlike areas such as hypertension where a given change in blood pressure is accepted as a surrogate for clinical events, it has to be recognized that in cachexia, the ‘relevance’ or ‘meaningfulness’ of a change in surrogates such as hand grip strength, stair‐climb power, leg extension strength or timed sit‐up‐and‐go is not known. For patients with heart failure, chronic kidney disease, stroke or ageing‐related frailty, such multimodal approaches are frequently considered, but evidence is so far weak compared with what has been achieved in COPD. F.S. reports unrestricted grants for clinical research from Celgene, Fresenius, and Helsinn, participation in Novartis lead clinical trial BYM338, and Punctual Advisorship (Boards, Expert meetings) Acacia, ACRAF, Amgen, Baxter, Celgene, Danone, Fresenius, GSK, Grünenthal, Helsinn, ISIS Global, Millennium/Takeda, Mundipharma, Novartis, Novelpharm, Nycomed, Obexia, Otsuka, Ono, Pharm‐Olam, Pfizer, Psioxus, PrIME, Santhera, Sunstone, Teva, Vifor.
PDF
