Expression of STAT3 and hypoxia markers in long-term surviving malignant glioma patients.

BACKGROUND: Glioblastoma is a malignant and aggressive type of central nevous system malignancy characterized by many distinct biological features including extensive hypoxia. Hypoxia in glioblatoma associates with complex signaling patterns including activation of several pathways such as MAPK, PI3K-AKT/mTOR and IL-6/JAK/STAT3 with the master regulator HIF-1, which in turn drive particular tumor behaviors determining, in the end, treatment outcomes and patients fate. Thus, the present study was designed to investigate the expression of selected hypoxia related factors including STAT3 in a small set of long-term surviving glioma patients. METHODS: The expression of selected hypoxia related factors including STAT3 was evaluated in a time series of formalin fixed paraffin embedded and cryopreserved glioma samples from repeatedly resected patients. In addition, comparative studies were also conducted on primary glioma cells derived from original patient samples, stabilized glioma cell lines and tumor-xenograft mice model. Obtained data were correlated with clinical findings too. RESULTS: Glioblastoma samples of the analyzed patients displayed heterogeneity in the expression of hypoxia- related and EMT markers with most interesting trend being observed in pSTAT3. This heterogeneity was subsequently confirmed in other employed models (primocultures derived from glioblastoma tissue resections, cryopreserved tumor specimens, stabilized glioblastoma cell line in vitro and in vivo) and concerned, in particular, STAT3 expression which remained stable. In addition, subsequent studies on the role of STAT3 in the context of glioblastoma hypoxia demonstrated opposing effects of its deletion on cell viability as well as the expression of hypoxia and EMT markers. CONCLUSIONS: Our results suport the importance of STAT3 expression and activity in the context of hypoxia in malignant glioblastoma long-term surviving glioma patients while emphasizing heterogeneity of biological outcomes in varying employed tumor models.

How an outbreak became a pandemic: a chronological analysis of crucial junctures and international obligations in the early months of the COVID-19 pandemic.

Understanding the spread of SARS-CoV-2, how and when evidence emerged, and the timing of local, national, regional, and global responses is essential to establish how an outbreak became a pandemic and to prepare for future health threats. With that aim, the Independent Panel for Pandemic Preparedness and Response has developed a chronology of events, actions, and recommendations, from December, 2019, when the first cases of COVID-19 were identified in China, to the end of March, 2020, by which time the outbreak had spread extensively worldwide and had been characterised as a pandemic. Datapoints are based on two literature reviews, WHO documents and correspondence, submissions to the Panel, and an expert verification process. The retrospective analysis of the chronology shows a dedicated initial response by WHO and some national governments, but also aspects of the response that could have been quicker, including outbreak notifications under the International Health Regulations (IHR), presumption and confirmation of human-to-human transmission of SARS-CoV-2, declaration of a Public Health Emergency of International Concern, and, most importantly, the public health response of many national governments. The chronology also shows that some countries, largely those with previous experience with similar outbreaks, reacted quickly, even ahead of WHO alerts, and were more successful in initially containing the virus. Mapping actions against IHR obligations, the chronology shows where efficiency and accountability could be improved at local, national, and international levels to more quickly alert and contain health threats in the future. In particular, these improvements include necessary reforms to international law and governance for pandemic preparedness and response, including the IHR and a potential framework convention on pandemic preparedness and response.

The nectar spur is not only a simple specialization for long-proboscid pollinators.

Since the time of Darwin, biologists have considered the floral nectar spur to be an adaptation representing a high degree of plant specialization. Nevertheless, some researchers suggest that nature is more complex and that even morphologically specialized plants attract a wide spectrum of visitors. We observed visitors on Impatiens burtonii (Balsaminaceae) and measured the depth of the proboscis insertion into the spur, the distance of the nectar surface from the spur entrance and the visitor's effectiveness. The hoverfly Melanostoma sp., with the shortest proboscis, was most active early in the morning and fed on pollen and nectar near the spur entrance. The honeybee Apis mellifera and the hoverfly Rhingia mecyana were the most frequent visitors before and after noon, respectively. Although R. mecyana, the only visitor able to reach the end of the spur, was the most frequent, it did not deposit the largest number of pollen grains per visit. Nectar spurs may function as complex structures allowing pollination by both short- and long-proboscid visitors and separating their spatial and temporal niches. Spurred plants should be considered as more generalized and exposed to more diverse selection pressures than previously believed.

Is the scaling relationship between carbohydrate storage and leaf biomass in meadow plants affected by the disturbance regime?

BACKGROUND AND AIMS: Below-ground carbohydrate storage is considered an adaptation of plants aimed at regeneration after disturbance. A theoretical model by Iwasa and Kubo was empirically tested which predicted (1) that storage of carbohydrates scales allometrically with leaf biomass and (2) when the disturbance regime is relaxed, the ratio of storage to leaf biomass increases, as carbohydrates are not depleted by disturbance. METHODS: These ideas were tested on nine herbaceous species from a temperate meadow and the disturbance regime was manipulated to create recently abandoned and mown plots. Just before mowing in June and at the end of the season in October, plants with below-ground organs were sampled. The material was used to assess the pool of total non-structural carbohydrates and leaf biomass. KEY RESULTS: In half of the cases, a mostly isometric relationship between below-ground carbohydrate storage and leaf biomass in meadow plants was found. The ratio of below-ground carbohydrate storage to leaf biomass did not change when the disturbance regime was less intensive than that for which the plants were adapted. CONCLUSIONS: These findings (isometric scaling relationship between below-ground carbohydrate storage and leaf biomass; no effect of a relaxed disturbance regime) imply that storage in herbs is probably governed by factors other than just the disturbance regime applied once in a growing season.

Asymmetric competition for nectar between a large nectar thief and a small pollinator: an energetic point of view.

There are two alternative hypotheses related to body size and competition for restricted food sources. The first one supposes that larger animals are superior competitors because of their increased feeding abilities, whereas the second one assumes superiority of smaller animals because of their lower food requirements. We examined the relationship between two unrelated species of different size, drinking technique, energy requirements and roles in plant pollination system, to reveal the features of their competitive interaction and mechanisms enabling their co-existence while utilising the same nectar source. We observed diurnal feeding behaviour of the main pollinator, the carpenter bee Xylocopa caffra and a nectar thief, the northern double-collared sunbird Cinnyris reichenowi on 19 clumps of Hypoestes aristata (Acanthaceae) in Bamenda Highlands, Cameroon. For comparative purpose, we established a simplistic model of daily energy expenditure and daily energy intake by both visitor species assuming that they spend all available daytime feeding on H. aristata. We revealed the energetic gain-expenditure balance of the studied visitor species in relation to diurnal changes in nectar quality and quantity. In general, smaller energy requirements and related ability to utilise smaller resources made the main pollinator X. caffra competitively superior to the larger nectar thief C. reichenowi. Nevertheless, sunbirds are endowed with several mechanisms to reduce asymmetry in exploitative competition, such as the use of nectar resources in times of the day when rivals are inactive, aggressive attacks on carpenter bees while defending the nectar plants, and higher speed of nectar consumption.

Prognostic Factors for Survival in Glioblastoma: A Retrospective Analysis Focused on the Role of Hemoglobin.

Background: Although several prognostic factors for survival have been identified in glioblastoma, there are numerous other potential markers (such as hemoglobin) whose role has not yet been confirmed. The aim of this study was to evaluate a wide range of potential prognostic factors, including HIF-1α and hemoglobin levels, for survival in glioblastoma. A secondary aim was to determine whether hemoglobin levels were associated with HIF-1α expression. Methods: A retrospective study of 136 patients treated for glioblastoma at our institution between 2012 and 2021 was performed. Cox univariate and multivariate analyses were carried out. Kaplan-Meier survival curves were generated. In addition, bivariate non-parametric correlation analyses were performed for key variables. Results: Median survival was 11.9 months (range: 0-119.4). According to the univariate analysis, 13 variables were significantly associated with survival: age, performance status, extent of surgery, tumor depth, tumor size, epilepsy, postoperative chemoradiotherapy, IDH mutations, CD44, HIF-1α, HIF-1ß, vimentin, and PDFGR. According to the multivariate regression analysis, only four variables remained significantly associated with survival: age, extent of surgery, epilepsy, and HIF-1α expression. No significant association was observed between hemoglobin levels (low <120 g/L in females or <140 g/L in males vs. high ≥120 or ≥140 g/L) and survival or HIF-1α/HIF-1ß expression. Conclusions: In this retrospective study of patients with glioblastoma, four variables-age, extent of surgery, HIF-1α expression, and epilepsy-were significant prognostic factors for survival. Hemoglobin levels were not significantly associated with survival or HIF-1α expression. Although hypoxia is a well-recognized component of the glioblastoma microenvironment, more research is needed to understand the pathogenesis of onset tumor hypoxia and treatment implication.

Diagnostic Utility of Immunohistochemical Detection of MEOX2, SOX11, INSM1 and EGFR in Gliomas.

Histological identification of dispersed glioma cells in small biopsies can be challenging, especially in tumours lacking the IDH1 R132H mutation or alterations in TP53. We postulated that immunohistochemical detection of proteins expressed preferentially in gliomas (EGFR, MEOX2, CD34) or during embryonal development (SOX11, INSM1) can be used to distinguish reactive gliosis from glioma. Tissue microarrays of 46 reactive glioses, 81 glioblastomas, 34 IDH1-mutant diffuse gliomas, and 23 gliomas of other types were analysed. Glial neoplasms were significantly more often (p < 0.001, χ2) positive for EGFR (34.1% vs. 0%), MEOX2 (49.3% vs. 2.3%), SOX11 (70.5% vs. 20.4%), and INSM1 (65.4% vs. 2.3%). In 94.3% (66/70) of the glioblastomas, the expression of at least two markers was observed, while no reactive gliosis showed coexpression of any of the proteins. Compared to IDH1-mutant tumours, glioblastomas showed significantly higher expression of EGFR, MEOX2, and CD34 and significantly lower positivity for SOX11. Non-diffuse gliomas were only rarely positive for any of the five markers tested. Our results indicate that immunohistochemical detection of EGFR, MEOX2, SOX11, and INSM1 can be useful for detection of glioblastoma cells in limited histological samples, especially when used in combination.

HIV prevention transformed: the new prevention research agenda.

We have entered a new era in HIV prevention whereby priorities have expanded from biomedical discovery to include implementation, effectiveness, and the effect of combination prevention at the population level. However, gaps in knowledge and implementation challenges remain. In this Review we analyse trends in the rapidly changing landscape of HIV prevention, and chart a new path for HIV prevention research that focuses on the implementation of effective and efficient combination prevention strategies to turn the tide on the HIV pandemic.

Towards an improved investment approach for an effective response to HIV/AIDS.

Substantial changes are needed to achieve a more targeted and strategic approach to investment in the response to the HIV/AIDS epidemic that will yield long-term dividends. Until now, advocacy for resources has been done on the basis of a commodity approach that encouraged scaling up of numerous strategies in parallel, irrespective of their relative effects. We propose a strategic investment framework that is intended to support better management of national and international HIV/AIDS responses than exists with the present system. Our framework incorporates major efficiency gains through community mobilisation, synergies between programme elements, and benefits of the extension of antiretroviral therapy for prevention of HIV transmission. It proposes three categories of investment, consisting of six basic programmatic activities, interventions that create an enabling environment to achieve maximum effectiveness, and programmatic efforts in other health and development sectors related to HIV/AIDS. The yearly cost of achievement of universal access to HIV prevention, treatment, care, and support by 2015 is estimated at no less than US$22 billion. Implementation of the new investment framework would avert 12·2 million new HIV infections and 7·4 million deaths from AIDS between 2011 and 2020 compared with continuation of present approaches, and result in 29·4 million life-years gained. The framework is cost effective at $1060 per life-year gained, and the additional investment proposed would be largely offset from savings in treatment costs alone.

Small RNA Sequencing Identifies PIWI-Interacting RNAs Deregulated in Glioblastoma-piR-9491 and piR-12488 Reduce Tumor Cell Colonies In Vitro.

Glioblastoma (GBM) is the most frequently occurring primary malignant brain tumor of astrocytic origin. To change poor prognosis, it is necessary to deeply understand the molecular mechanisms of gliomagenesis and identify new potential biomarkers and therapeutic targets. PIWI-interacting RNAs (piRNAs) help in maintaining genome stability, and their deregulation has already been observed in many tumors. Recent studies suggest that these molecules could also play an important role in the glioma biology. To determine GBM-associated piRNAs, we performed small RNA sequencing analysis in the discovery set of 19 GBM and 11 non-tumor brain samples followed by TaqMan qRT-PCR analyses in the independent set of 77 GBM and 23 non-tumor patients. Obtained data were subsequently bioinformatically analyzed. Small RNA sequencing revealed 58 significantly deregulated piRNA molecules in GBM samples in comparison with non-tumor brain tissues. Deregulation of piR-1849, piR-9491, piR-12487, and piR-12488 was successfully confirmed in the independent groups of patients and controls (all p < 0.0001), and piR-9491 and piR-12488 reduced GBM cells' ability to form colonies in vitro. In addition, piR-23231 was significantly associated with the overall survival of the GBM patients treated with Stupp regimen (p = 0.007). Our results suggest that piRNAs could be a novel promising diagnostic and prognostic biomarker in GBM potentially playing important roles in gliomagenesis.

Health systems resilience in managing the COVID-19 pandemic: lessons from 28 countries.

Health systems resilience is key to learning lessons from country responses to crises such as coronavirus disease 2019 (COVID-19). In this perspective, we review COVID-19 responses in 28 countries using a new health systems resilience framework. Through a combination of literature review, national government submissions and interviews with experts, we conducted a comparative analysis of national responses. We report on domains addressing governance and financing, health workforce, medical products and technologies, public health functions, health service delivery and community engagement to prevent and mitigate the spread of COVID-19. We then synthesize four salient elements that underlie highly effective national responses and offer recommendations toward strengthening health systems resilience globally.

Are Reproductive Traits Related to Pollen Limitation in Plants? A Case Study from a Central European Meadow.

The deficiency of pollen grains for ovule fertilization can be the main factor limiting plant reproduction and fitness. Because of the ongoing global changes, such as biodiversity loss and landscape fragmentation, a better knowledge of the prevalence and predictability of pollen limitation is challenging within current ecological research. In our study we used pollen supplementation to evaluate pollen limitation (at the level of seed number and weight) in 22 plant species growing in a wet semi-natural meadow. We investigated the correlation between the pollen limitation index (PL) and floral traits associated with plant reproduction or pollinator foraging behavior. We recorded significant pollen limitation for approximately 41% of species (9 out of 22 surveyed). Seven species had a significant positive response in seed production and two species increased in seed weight after pollen supplementation. Considering traits, PL significantly decreased with the number of pollinator functional groups. The relationship of PL with other examined traits was not supported by our results. The causes of pollen limitation may vary among species with regard to (1) different reproductive strategies and life history, and/or (2) temporary changes in influence of biotic and abiotic factors at a site.

Coming to terms with complexity: a call to action for HIV prevention.

A quarter of a century of AIDS responses has created a huge body of knowledge about HIV transmission and how to prevent it, yet every day, around the world, nearly 7000 people become infected with the virus. Although HIV prevention is complex, it ought not to be mystifying. Local and national achievements in curbing the epidemic have been myriad, and have created a body of evidence about what works, but these successful approaches have not yet been fully applied. Essential programmes and services have not had sufficient coverage; they have often lacked the funding to be applied with sufficient quality and intensity. Action and funding have not necessarily been directed to where the epidemic is or to what drives it. Few programmes address vulnerability to HIV and structural determinants of the epidemic. A prevention constituency has not been adequately mobilised to stimulate the demand for HIV prevention. Confident and unified leadership has not emerged to assert what is needed in HIV prevention and how to overcome the political, sociocultural, and logistic barriers in getting there. We discuss the combination of solutions which are needed to intensify HIV prevention, using the existing body of evidence and the lessons from our successes and failures in HIV prevention.

No clear clinical benefit of using mini-invasive extracorporeal circulation in coronary artery bypass grafting in low-risk patients.

BACKGROUND: Current research is engaged in innovative technologies of extracorporeal circulation (ECC) systems in an effort to eliminate negative effects. Some studies have shown that, due to the complexity of technical settings of mini-ECC, they invoke a weaker immune response compared to classic ECC. The clinical benefits of using these systems have not been clearly proven yet. METHODS: A group of 54 patients who were indicated for elective coronary surgery were randomised into two groups - Group A (patients operated on using classic ECC - open modification) and Group B (patients operated on using mini-ECC). The concentrations of IL-6, PMN elastase and MCP-1 in both groups were monitored per- and postoperatively, along with the postoperative clinical course. RESULTS: The groups did not differ in the basic pre- and peroperative characteristics. We recorded a lower priming for mini-ECC (p < 0.001) and significantly reduced hemodilution during ECC. There were no differences in the clinical outcome in either group. Serum concentrations of monitored markers of immune reaction towards ECC showed higher activity during standard ECC. CONCLUSION: New technologies used in mini-systems have proven to lower activation of the immune system, which can be monitored using kinetics of proinflammatory mediators. In spite of these comparable laboratory results, we did not find differences in short-term clinical results when comparing both these groups of low-risk patients.

The potential benefit of intracarpal pressure measurement in endoscopic carpal tunnel syndrome surgery--an analysis of EMG findings and pressure values.

Endoscopic carpal tunnel syndrome surgery is a modern minimally invasive method of carpal tunnel decompression. However, the method does also have its critics, who emphasize that there is an increased rate of complications in comparison to open procedures. To further improve and optimize results of endoscopic surgery we used an intracarpal pressure sensor to verify the effect of carpal tunnel decompression. The endoscopic single portal approach was used in all cases. Median nerve conduction studies were performed prior to and 3 months after surgery. Two groups, those with pressure studies and those without, were then compared according to several EMG parameters such as: median nerve distal motor latency, amplitude of motor response, sensory nerve conduction velocity to the index finger, and amplitude of sensory nerve action potential. In both groups, we observed similarly significant improvements in all conduction parameters, except the amplitude of motor response, which did not change in either group, i.e. no difference in postoperative EMG between the two groups was observed. Despite this fact, intracarpal pressure measurement is still useful in localising the point in which the median nerve is compressed and provides valuable functional information on the level decompression achieved.

Surgical Pleth Index and Analgesia Nociception Index for intraoperative analgesia in patients undergoing neurosurgical spinal procedures: a comparative randomized study.

BACKGROUND: The Surgical Plethysmographic Index (SPI) and the Analgesia Nociception Index (ANI) have been suggested for the non-invasive intraoperative monitoring of nociception/anti-nociception balance. We aimed to compare patterns of intraoperative use of opioids, postoperative cortisol levels and postoperative pain scores after intraoperative analgesia guided either by ANI, SPI or anesthesiologist's judgment. METHODS: Seventy-two adult ASA I-III patients scheduled for elective neurosurgical spinal procedures were randomized into the ANI group, SPI group and control group. Anesthesia and intraoperative use of opioids (sufentanil boluses based on body weight) were managed according to a strict protocol. The use of sufentanil was targeted to keep ANI value 50-70 in the ANI group, SPI value below individual postinduction baseline value plus 10 points in the SPI group. In the control group, the use of opioids was left at anesthesiologist's discretion. RESULTS: Additional sufentanil boluses were administered earlier in the ANI and SPI groups in comparison to the control group (third dose after 51.8±22.1 vs. 52.7±14.8 vs. 84.5±24.8 min respectively, P=0.001; fourth dose after 61.3±30.1 vs. 57.2±14.1 vs. 120.0±26.2 min, P=0.003, and fifth dose after 78.8±33.7 vs. 74.0±11.6 vs. 146.7±23.2 min respectively, P=0.009). There were no differences in postoperative cortisol levels, time to spontaneous breathing at the end of anesthesia and postoperative pain scores. CONCLUSIONS: Both ANI and SPI guidance significantly modified intraoperative opioid use, but no modification of postoperative cortisol levels and postoperative pain was observed.

The role of ultraviolet reflectance and pattern in the pollination system of Hypoxis camerooniana (Hypoxidaceae).

Apart from floral morphology and colours perceived by the human eye, ultraviolet (UV) reflectance acts as an important visual advertisement of numerous flowering plant species for pollinators. However, the effect of UV signalling on attracting pollinators of particular plant species is still insufficiently studied, especially in the Afrotropics. Therefore, we studied the pollination system of Hypoxis camerooniana in montane grasslands of Mount Cameroon, West/Central Africa. We focused mainly on the effects of the flowers' UV reflectance on its visitors. We experimentally removed UV reflection from petals either completely or partially. Thereafter, flower visitors were recorded and pistils were collected post-flowering to quantify germinated pollen tubes per treatments. The most important visitors were bees, followed by flies. Due to their contacts with reproductive organs bees are considered as the primary pollinators. Visitation rates were lower when UV reflectance was completely removed, whereas the decrease of frequency on half-treated flowers did not differ significantly from control treatments. The complete removal of UV also affected bees' landing behaviour, but not that of flies. We showed that the presence of UV reflectance is more important than UV pattern for bees visiting flowers of H. camerooniana. We hypothesize that exploiting all flowers irrespective of their pattern can be more efficient for pollinators in the open grasslands of high altitudes to spot these relatively scarce flowers by their UV reflectance. Furthermore, we highlight the necessity of both experimental and natural controls in similar studies to control for additional effects of the used UV manipulations. Many plants advertise their flowers with UV reflectance visible to their insect visitors. By manipulating the UV reflectance and pattern of Hypoxis camerooniana in the Afromontane grasslands of Mount Cameroon, we have shown how crucial it is for the predominant visitor, bees. Both bees' preferences for flowers and their behaviour during visits are influenced by changes in UV reflectance. However, the presence of some UV signal is more important than the specific pattern. Especially in montane grasslands with higher UV irradiation, the UV floral colours are important for recognition of flowers by potential pollinators.

Factors associated with 'feeling suicidal': the role of sexual identity.

This paper examines factors associated with feeling suicidal in a large sample of urban men in Sydney and Melbourne, aged 18-50, including heterosexual, gay and bisexual men, HIV antibody positive and HIV antibody negative. As in previous research, sexuality (being homosexual or bisexual) was found to be a major predictor of suicidality. The research went some way towards explaining the close relationship between feeling suicidal and sexual orientation. Sexuality interacts with feeling bad in that, once men feel moderately bad/depressed, they are more likely to feel suicidal if they are homosexual or bisexual than if they are heterosexual. In addition, the research found that experience of verbal abuse and physical assault (harassment) increased feeling suicidal for both heterosexual and gay/bisexual men, not just for homosexual men as suggested by previous research, and that social isolation in the form of living alone is a further risk factor. Seeking counseling help and taking sexual risks were also independently associated with feeling suicidal. These actions may result from feeling suicidal rather than the reverse, and their association with feeling suicidal warrants further research. Many of the 46 independent variables examined in the research, including HIV antibody status and closeness to the HIV/ AIDS epidemic, were related to feeling suicidal only through their association with being gay/bisexual. Celibacy and general risk taking were not related to feeling suicidal in this study.