Exploring immune status in peripheral blood and tumor tissue in association with survival in patients with multi-organ metastatic colorectal cancer

Colorectal cancer (CRC) raises considerable clinical challenges, including a high mortality rate once the tumor spreads to distant sites. At this advanced stage, more accurate prediction of prognosis and treatment outcome is urgently needed. The role of cancer immunity in metastatic CRC (mCRC) is poorly understood. Here, we explore cellular immune cell status in patients with multi-organ mCRC. We analyzed T cell infiltration in primary tumor sections, surveyed the lymphocytic landscape of liver metastases, and assessed circulating mononuclear immune cells. Besides asking whether immune cells are associated with survival at this stage of the disease, we investigated correlations between the different tissue types; as this could indicate a dominant immune phenotype. Taken together, our analyses corroborate previous observations that higher levels of CD8+ T lymphocytes link to better survival outcomes. Our findings therefore extend evidence from earlier stages of CRC to indicate an important role for cancer immunity in disease control even after metastatic spreading to multiple organs. This finding may help to improve predicting outcome of patients with mCRC and suggests a future role for immunotherapeutic strategies.</p

Ventilation and thermal conditions in secondary schools in the Netherlands: Effects of COVID-19 pandemic control and prevention measures

During the COVID-19 pandemic, the importance of ventilation was widely stressed and new protocols of ventilation were implemented in school buildings worldwide. In the Netherlands, schools were recommended to keep the windows and doors open, and after a national lockdown more stringent measures such as reduction of occupancy were introduced. In this study, the actual effects of such measures on ventilation and thermal conditions were investigated in 31 classrooms of 11 Dutch secondary schools, by monitoring the indoor and outdoor CO 2 concentration and air temperature, both before and after the lockdown. Ventilation rates were calculated using the steady-state method. Pre-lockdown, with an average occupancy of 17 students, in 42% of the classrooms the CO 2 concentration exceeded the upper limit of the Dutch national guidelines (800 ppm above outdoors), while 13% had a ventilation rate per person (VR p) lower than the minimum requirement (6 l/s/p). Post-lockdown, the indoor CO 2 concentration decreased significantly while for ventilation rates significant increase was only found in VR p, mainly caused by the decrease in occupancy (average 10 students). The total ventilation rate per classrooms, mainly induced by opening windows and doors, did not change significantly. Meanwhile, according to the Dutch national guidelines, thermal conditions in the classrooms were not satisfying, both pre- and post-lockdown. While opening windows and doors cannot achieve the required indoor environmental quality at all times, reducing occupancy might not be feasible for immediate implementation. Hence, more controllable and flexible ways for improving indoor air quality and thermal comfort in classrooms are needed

SARS-CoV-2 outbreaks in secondary school settings in the Netherlands during fall 2020: silent circulation

BACKGROUND: In fall 2020 when schools in the Netherlands operated under a limited set of COVID-19 measures, we conducted outbreaks studies in four secondary schools to gain insight in the level of school transmission and the role of SARS-CoV-2 transmission via air and surfaces. METHODS: Outbreak studies were performed between 11 November and 15 December 2020 when the wild-type variant of SARS-CoV-2 was dominant. Clusters of SARS-CoV-2 infections within schools were identified through a prospective school surveillance study. All school contacts of cluster cases, irrespective of symptoms, were invited for PCR testing twice within 48 h and 4-7 days later. Combined NTS and saliva samples were collected at each time point along with data on recent exposure and symptoms. Surface and active air samples were collected in the school environment. All samples were PCR-tested and sequenced when possible. RESULTS: Out of 263 sampled school contacts, 24 tested SARS-CoV-2 positive (secondary attack rate 9.1%), of which 62% remained asymptomatic and 42% had a weakly positive test result. Phylogenetic analysis on 12 subjects from 2 schools indicated a cluster of 8 and 2 secondary cases, respectively, but also other distinct strains within outbreaks. Of 51 collected air and 53 surface samples, none were SARS-CoV-2 positive. CONCLUSION: Our study confirmed within school SARS-CoV-2 transmission and substantial silent circulation, but also multiple introductions in some cases. Absence of air or surface contamination suggests environmental contamination is not widespread during school outbreaks

Long-Lasting, Pathway-Specific Impairment of a Novel Form of Spike-Timing-Dependent Long-Term Depression by Neuropathic Pain in the Anterior Cingulate Cortex

Malfunctioning synaptic plasticity is one of the major mechanisms contributing to the development of chronic pain. We studied spike-timing dependent depression (tLTD) in the anterior cingulate cortex (ACC) of male mice, a brain region involved in processing emotional aspects of pain. tLTD onto layer 5 pyramidal neurons depended on postsynaptic calcium-influx through GluN2B-containing NMDARs and retrograde signaling via nitric oxide to reduce presynaptic release probability. After chronic constriction injury of the sciatic nerve, a model for neuropathic pain, tLTD was rapidly impaired; and this phenotype persisted even beyond the time of recovery from mechanical sensitization. Exclusion of GluN2B-containing NMDARs from the postsynaptic site specifically at projections from the anterior thalamus to the ACC caused the tLTD phenotype, whereas signaling downstream of nitric oxide synthesis remained intact. Thus, transient neuropathic pain can leave a permanent trace manifested in the disturbance of synaptic plasticity in a specific afferent pathway to the cortex. SIGNIFICANCE STATEMENT Synaptic plasticity is one of the main mechanisms that contributes to the development of chronic pain. Most studies have focused on potentiation of excitatory synaptic transmission, but very little is known about the reduction in synaptic strength. We have focused on the ACC, a brain region associated with the processing of emotional and affective components of pain. We studied spike-timing dependent LTD, which is a biologically plausible form of synaptic plasticity, that depends on the relative timing of presynaptic and postsynaptic activity. We found a long-lasting and pathway-specific suppression of the induction mechanism for spike-timing dependent LTD from the anterior thalamus to the ACC, suggesting that this pathology might be involved in altered emotional processing in pain

SARS‑CoV‑2 incidence in secondary schools: the role of national and school‑initiated COVID‑19 measures

Introduction: Our aim was to gain insight into the effect of COVID-19 measures on SARS-CoV-2 incidence in secondary schools and the association with classroom CO 2 concentration and airborne contamination. Methods: Between October 2020—June 2021, 18 schools weekly reported SARS-CoV-2 incidence and completed surveys on school-initiated COVID-19 measures (e.g. improving hygiene or minimizing contacts). CO 2 was measured in occupied classrooms twice, and SARS-CoV-2 air contamination longitudinally using electrostatic dust collectors (EDC) and analyzed using RT-qPCR. National COVID-19 policy measures varied during pre-lockdown, lockdown and post-lockdown periods. During the entire study, schools were recommended to improve ventilation. SARS-CoV-2 incidence rate ratios (IRR) were estimated by Generalized Estimating Equation (GEE) models. Results: During 18 weeks follow-up (range: 10–22) SARS-CoV-2 school-incidence decreased during national lockdown (adjusted IRR: 0.41, 95%CI: 0.21–0.80) and post-lockdown (IRR: 0.60, 0.39–0.93) compared to pre-lockdown. School-initiated COVID-19 measures had no additional effect. Pre-lockdown, IRRs per 10% increase in time CO 2 exceeded 400, 550 and 800 ppm above outdoor level respectively, were 1.08 (1.00–1.16), 1.10 (1.02–1.19), and 1.08 (0.95–1.22). Post-lockdown, CO 2-concentrations were considerably lower and not associated with SARS-CoV-2 incidence. No SARS-CoV-2 RNA was detected in any of the EDC samples. Conclusion: During a period with low SARS-CoV-2 population immunity and increased attention to ventilation, with CO 2 levels most of the time below acceptable thresholds, only the national policy during and post-lockdown of reduced class-occupancy, stringent quarantine, and contact testing reduced SARS-CoV-2 incidence in Dutch secondary schools. Widespread SARS-CoV-2 air contamination could not be demonstrated in schools under the prevailing conditions during the study. Environmental & Climate Desig

Ventilation and thermal conditions in secondary schools in the Netherlands: Effects of COVID-19 pandemic control and prevention measures

During the COVID-19 pandemic, the importance of ventilation was widely stressed and new protocols of ventilation were implemented in school buildings worldwide. In the Netherlands, schools were recommended to keep the windows and doors open, and after a national lockdown more stringent measures such as reduction of occupancy were introduced. In this study, the actual effects of such measures on ventilation and thermal conditions were investigated in 31 classrooms of 11 Dutch secondary schools, by monitoring the indoor and outdoorCO2 concentration and air temperature, both before and after the lockdown. Ventilation rates were calculated using the steady-state method. Pre-lockdown, with an average occupancy of 17 students, in 42% of the classrooms the CO2 concentration exceeded the upper limit of the Dutch national guidelines (800 ppm above outdoors),while 13% had a ventilation rate per person (VRp) lower than the minimum requirement (6 l/s/p). Post lockdown, the indoor CO2 concentration decreased significantly while for ventilation rates significant increase was only found in VRp, mainly caused by the decrease in occupancy (average 10 students). The total ventilation rate per classrooms, mainly induced by opening windows and doors, did not change significantly. Meanwhile, according to the Dutch national guidelines, thermal conditions in the classrooms were not satisfying, both pre and post-lockdown. While opening windows and doors cannot achieve the required indoor environmental quality at all times, reducing occupancy might not be feasible for immediate implementation. Hence, more controllable and flexible ways for improving indoor air quality and thermal comfort in classrooms are needed.Indoor EnvironmentUrban Data Scienc

SARS-CoV-2 outbreaks in secondary school settings in the Netherlands during fall 2020: silent circulation

BACKGROUND: In fall 2020 when schools in the Netherlands operated under a limited set of COVID-19 measures, we conducted outbreaks studies in four secondary schools to gain insight in the level of school transmission and the role of SARS-CoV-2 transmission via air and surfaces. METHODS: Outbreak studies were performed between 11 November and 15 December 2020 when the wild-type variant of SARS-CoV-2 was dominant. Clusters of SARS-CoV-2 infections within schools were identified through a prospective school surveillance study. All school contacts of cluster cases, irrespective of symptoms, were invited for PCR testing twice within 48 h and 4-7 days later. Combined NTS and saliva samples were collected at each time point along with data on recent exposure and symptoms. Surface and active air samples were collected in the school environment. All samples were PCR-tested and sequenced when possible. RESULTS: Out of 263 sampled school contacts, 24 tested SARS-CoV-2 positive (secondary attack rate 9.1%), of which 62% remained asymptomatic and 42% had a weakly positive test result. Phylogenetic analysis on 12 subjects from 2 schools indicated a cluster of 8 and 2 secondary cases, respectively, but also other distinct strains within outbreaks. Of 51 collected air and 53 surface samples, none were SARS-CoV-2 positive. CONCLUSION: Our study confirmed within school SARS-CoV-2 transmission and substantial silent circulation, but also multiple introductions in some cases. Absence of air or surface contamination suggests environmental contamination is not widespread during school outbreaks

High <i>ABCC2</i> and Low <i>ABCG2</i> Gene Expression Are Early Events in the Colorectal Adenoma-Carcinoma Sequence

<div><p>Development of colorectal cancer (CRC) may result from a dysfunctional interplay between diet, gut microbes and the immune system. The ABC transport proteins ABCB1 (P-glycoprotein, Multidrug resistance protein 1, MDR1), ABCC2 (MRP2) and ABCG2 (BCRP) are involved in transport of various compounds across the epithelial barrier. Low mRNA level of <i>ABCB1</i> has previously been identified as an early event in colorectal carcinogenesis (Andersen et al., PLoS One. 2013 Aug 19;8(8):e72119).</p><p><i>ABCC2</i> and <i>ABCG2</i> mRNA levels were assessed in intestinal tissue from 122 CRC cases, 106 adenoma cases (12 with severe dysplasia, 94 with mild-moderate dysplasia) and from 18 controls with normal endoscopy.</p><p>We found significantly higher level of <i>ABCC2</i> in adenomas with mild to moderate dysplasia and carcinoma tissue compared to the levels in unaffected tissue from the same individual (P = 0.037, P = 0.037, and P<0.0001) and in carcinoma and distant unaffected tissue from CRC cases compared to the level in the healthy individuals (P = 0.0046 and P = 0.036). Furthermore, <i>ABCG2</i> mRNA levels were significantly lower in adenomas and carcinomas compared to the level in unaffected tissue from the same individuals and compared to tissue from healthy individuals (P<0.0001 for all). The level of <i>ABCB2</i> in adjacent normal tissue was significantly higher than in tissue from healthy individuals (P = 0.011).</p><p>In conclusion, this study found that <i>ABCC2</i> and <i>ABCG2</i> expression levels were altered already in mild/moderate dysplasia in carcinogenesis suggesting that these ABC transporters are involved in the early steps of carcinogenesis as previously reported for <i>ABCB1</i>. These results suggest that dysfunctional transport across the epithelial barrier may contribute to colorectal carcinogenesis.</p></div