Changes in gene expression patterns in the tumor microenvironment of head and neck squamous cell carcinoma under chemoradiotherapy depend on response

Chemoradiotherapy (CRT) is a standard treatment for advanced head and neck squamous cell carcinoma (HNSCC). Unfortunately, not all patients respond to this therapy and require further treatment, either salvage surgery or palliative therapy. The addition of immunotherapy to CRT is currently being investigated and early results describe a mixed response. Therefore, it is important to understand the impact of CRT on the tumor microenvironment (TME) to be able to interpret the results of the clinical trials. Paired biopsies from 30 HNSCC patients were collected before and three months after completion of primary CRT and interrogated for the expression of 1392 immune- and cancer-related genes. There was a relevant difference in the number of differentially expressed genes between the total cohort and patients with residual disease. Genes involved in T cell activation showed significantly reduced expression in these tumors after therapy. Furthermore, gene enrichment for several T cell subsets confirmed this observation. The analysis of tissue resident memory T cells (TRM) did not show a clear association with impaired response to therapy. CRT seems to lead to a loss of T cells in patients with incomplete response that needs to be reversed. It is not clear whether the addition of anti-PD-1 antibodies alone to CRT can prevent treatment failure, as no upregulation of the targets was measurable in the TME

Prospective longitudinal study of immune checkpoint molecule (ICM) expression in immune cell subsets during curative conventional therapy of head and neck squamous cell carcinoma (HNSCC)

Programmed-death-1 (PD1) antibodies are approved for recurrent and metastatic head and neck squamous cell carcinoma. Multiple drugs targeting costimulatory and coinhibitory immune checkpoint molecules (ICM) have been discovered. However, it remains unknown how these ICM are affected by curative conventional therapy on different immune cell subsets during the course of treatment. In the prospective noninterventional clinical study titled “Immune Response Evaluation to Curative conventional Therapy” (NCT03053661), 22 patients were prospectively enrolled. Blood samples were drawn at defined time points throughout curative conventional treatment and follow-up. Immune cells (IC) from the different time points were assessed by multicolor flow cytometry. The following ICM were measured by flow cytometry: PD1, CTLA4, BTLA, CD137, CD27, GITR, OX40, LAG3 and TIM3. Dynamics of ICM expression were assessed using nonparametric paired samples tests. Significant changes were noted for PD1, BTLA and CD27 on multiple IC types during or after radiotherapy. Nonsignificant trends for increased expression of OX40 and GITR from baseline until the end of RT were observed on CD4 T cells and CD4+ CD39+ T cells. In patients with samples at recurrence of disease, a nonsignificant increase of TIM3 and LAG3 positive CD4+ CD39+ T cells was evident, accompanied by an increase of double positive cells for TIM3/LAG3. Potential future targets to be combined with RT in the conventional treatment and anti-PD1/PD-L could be BTLA agonists, or agonistic antibodies to costimulatory ICM like CD137, OX40 or GITR. The combination of cetuximab with CD27 agonistic antibodies enhancing ADCC or the targeting of TIM3/LAG3 may be another promising strategy

Increasing mean age of head and neck cancer patients at a German tertiary referral center

Background: The impact of demographic change on the age at diagnosis in German head and neck cancer (HNC) patients is unclear. Here we present an evaluation of aging trends in HNC at a tertiary referral center. Methods: Retrospective cohort study on aging trends at the initial diagnosis of newly diagnosed patients with HNC between 2004 and 2018 at the head and neck cancer center Ulm in relation to demographic data of the catchment area. Results: The study population consisted of 2450 individuals diagnosed with HNC with a mean age of 62.84 (±11.67) years. We observed a significant increase in annual incidence rates and mean age over time. Mean age among HNC patients increased significantly more than among the population in the catchment area. Whereas the incidence rate of patients <50 years did not change, the incidence of HNC patients aged ≥70 years increased the most. The mean patient age in the main tumor sites increased significantly. Surprisingly, HPV-positive patients were not younger than HPV-negative patients, but showed a non-significant trend towards a higher mean age (63.0 vs. 60.7 years). Conclusions: Increasing incidence rates in older patients pose a challenge for health care systems. A nationwide study is needed to assess the dynamics and impact of aging on the incidence of HNC

BTK isoforms p80 and p65 are expressed in head and neck squamous cell carcinoma (HNSCC) and involved in tumor progression

Here, we describe the expression of Bruton’s Tyrosine Kinase (BTK) in head and neck squamous cell carcinoma (HNSCC) cell lines as well as in primary HNSCC samples. BTK is a kinase initially thought to be expressed exclusively in cells of hematopoietic origin. Apart from the 77 kDa BTK isoform expressed in immune cells, particularly in B cells, we identified the 80 kDa and 65 kDa BTK isoforms in HNSCC, recently described as oncogenic. Importantly, we revealed that both isoforms are products of the same mRNA. By investigating the mechanism regulating oncogenic BTK-p80/p65 expression in HNSSC versus healthy or benign tissues, our data suggests that the epigenetic process of methylation might be responsible for the initiation of BTK-p80/p65 expression in HNSCC. Our findings demonstrate that chemical or genetic abrogation of BTK activity leads to inhibition of tumor progression in terms of proliferation and vascularization in vitro and in vivo. These observations were associated with cell cycle arrest and increased apoptosis and autophagy. Together, these data indicate BTK-p80 and BTK-p65 as novel HNSCC-associated oncogenes. Owing to the fact that abundant BTK expression is a characteristic feature of primary and metastatic HNSCC, targeting BTK activity appears as a promising therapeutic option for HNSCC patients

Uppdatering av den vetenskapliga grunden för klimatarbetet

Det naturvetenskapliga kunskapsläget om klimatförändringarna förbättrats ständigt genomforskningen om klimatsystemet, klimatpåverkan, klimatets variationer och förändringar samtklimateffekter.Kunskapsläget är väletablerat när det gäller den grundläggande fysiken bakom växthuseffekten,liksom att genomsnittstemperaturen vid jordytan stigit de senaste femtio åren. Det är ocksåmycket sannolikt att det mesta av den observerade uppvärmningen beror på mänskligklimatpåverkan.Samtidigt finns det betydande osäkerheter när det gäller konsekvenserna av klimatförändringarnasamt hur mycket utsläppen behöver minska för att man ska nå ett givetklimatmål. Värdet på klimatkänsligheten är den viktigaste faktorn för beräkningar av hurmycket växthusgaser vi kan släppa ut, givet ett visst temperaturmål.Forskningen visar att det behövs stora och snabba utsläppsminskningar för att uppnåtvågradersmålet. För att nå ett lägre temperaturmål, till exempel ett 1,5-gradersmål, är denödvändiga utsläppsminskningarna än mer omfattande. För att nå tvågradersmålet med en sannolikhet runt 70 % krävs uppskattningsvis att deglobala växthusgasutsläppen minskar i storleksordningen 50‒60 % från år 2000 till 2050,och minskar med nära 100 % till 2100. För att nå ett 1,5-gradersmål med en sannolikhet runt 70 % krävs globala nollutsläpp redanrunt år 2050. För att nå ett 1,5-gradersmål med en sannolikhet runt 50 % krävs uppskattningsvis att deglobala växthusgasutsläppen minskar i storleksordningen 80 % från år 2000 till 2050, ochmed nära 100 % till 2100.Det är framför allt de kumulativa utsläppen av koldioxid och andra långlivade växthusgaser somräknas när det gäller hur stora klimatförändringarna blir bortom 2100. Ju senare de globalautsläppen kulminerar, och ju högre nivå de då är på, desto större blir utmaningen för attåstadkomma en tillräckligt snabb påföljande utsläppsminskningstakt. Reducerade utsläpp avkortlivade klimatpåverkande ämnen är viktigt främst i ett kortare perspektiv.Det finns olika modeller för hur de globala utsläppsminskningarna kan fördelas mellan olikaregioner och länder. Dessa baseras inte på naturvetenskapliga principer utan är beroende avpolitiska och andra ställningstaganden. För en del länder skiljer sig resultaten mycket beroendepå valet av fördelningsmodell. För de flesta industriländer är slutsatsen dock generellt settdensamma: jämfört med idag behöver deras utsläpp minska mycket kraftigt. För att nå tvågradersmålet med i storleksordningen 70 % sannolikhet krävs, givet en globaltlika per capita fördelning av utsläppen från och med 2050, att utsläppen i Sverige minskarmed cirka 70 % från år 2005 till 2050. Den motsvarande siffran för EU är cirka 80 %. För att nå ett 1,5-gradersmål med i storleksordningen 70 % sannolikhet krävs, givet englobalt lika per capita fördelning av utsläppen från och med 2050, att utsläppen minskarfrån år 2005 till år 2050 med runt 100 % i Sverige och i EU, och i andra länder. För att nå ett 1,5-gradersmål med i storleksordningen 50 % sannolikhet krävs, givet englobalt lika per capita fördelning av utsläppen från och med 2050, att utsläppen i Sverigeoch EU minskar med drygt 90 % från år 2005 till 2050.Nettoutsläpp av koldioxid från avskogning och utrikes luft- och sjöfart ingår inte i dessauppskattningar.Generellt blir riskerna för allvarliga klimateffekter mindre ju mer ambitiöst temperaturmål somväljs, men riskerna försvinner inte med tvågradersmålet, och inte ens med ett 1,5-gradersmål.Jämfört med IPCC:s AR4 från 2007, har nya forskningsresultat publicerats om klimateffekter. Idenna rapport har vi fokuserat på havsnivåhöjningen, havsförsurningen, den biologiskamångfalden samt klimateffekter i Arktis. Jämfört med genomgången av kunskapsläget i AR4visar nya resultat att den framtida havsnivåhöjningen kan bli större, havsförsurningens effekterpå marina ekosystem omfattande och även om en del arter kan vara anpassningsbara, kanvärldens ekosystem påverkas av skillnader i olika arters sårbarhet för klimatförändringarna. IArktis sker snabba förändringar.Sammantaget ter sig riskerna för allvarliga klimateffekter större jämfört med AR4.Denna rapport utgår från naturvetenskaplig klimatforskning sedan 2007. Rapporten förordar inte något specifikt temperaturmål, någon specifik utsläppsbana eller specifika policybeslut. Dessaär föremål för politiska avgöranden

Intelligent Hydrogels in Myocardial Regeneration and Engineering

Myocardial infarction (MI) causes impaired cardiac function due to the loss of cardiomyocytes following an ischemic attack. Intelligent hydrogels offer promising solutions for post-MI cardiac tissue therapy to aid in structural support, contractility, and targeted drug therapy. Hydrogels are porous hydrophilic matrices used for biological scaffolding, and upon the careful alteration of ideal functional groups, the hydrogels respond to the chemistry of the surrounding microenvironment, resulting in intelligent hydrogels. This review delves into the perspectives of various intelligent hydrogels and evidence from successful models of hydrogel-assisted treatment strategies

Changes in Gene Expression Patterns in the Tumor Microenvironment of Head and Neck Squamous Cell Carcinoma Under Chemoradiotherapy Depend on Response

Chemoradiotherapy (CRT) is a standard treatment for advanced head and neck squamous cell carcinoma (HNSCC). Unfortunately, not all patients respond to this therapy and require further treatment, either salvage surgery or palliative therapy. The addition of immunotherapy to CRT is currently being investigated and early results describe a mixed response. Therefore, it is important to understand the impact of CRT on the tumor microenvironment (TME) to be able to interpret the results of the clinical trials. Paired biopsies from 30 HNSCC patients were collected before and three months after completion of primary CRT and interrogated for the expression of 1392 immune- and cancer-related genes. There was a relevant difference in the number of differentially expressed genes between the total cohort and patients with residual disease. Genes involved in T cell activation showed significantly reduced expression in these tumors after therapy. Furthermore, gene enrichment for several T cell subsets confirmed this observation. The analysis of tissue resident memory T cells (T(RM)) did not show a clear association with impaired response to therapy. CRT seems to lead to a loss of T cells in patients with incomplete response that needs to be reversed. It is not clear whether the addition of anti-PD-1 antibodies alone to CRT can prevent treatment failure, as no upregulation of the targets was measurable in the TME

Prospective longitudinal study of immune checkpoint molecule (ICM) expression in immune cell subsets during curative conventional therapy of head and neck squamous cell carcinoma (HNSCC)

Programmed-death-1 (PD1) antibodies are approved for recurrent and metastatic head and neck squamous cell carcinoma. Multiple drugs targeting costimulatory and coinhibitory immune checkpoint molecules (ICM) have been discovered. However, it remains unknown how these ICM are affected by curative conventional therapy on different immune cell subsets during the course of treatment. In the prospective noninterventional clinical study titled “Immune Response Evaluation to Curative conventional Therapy” (NCT03053661), 22 patients were prospectively enrolled. Blood samples were drawn at defined time points throughout curative conventional treatment and follow-up. Immune cells (IC) from the different time points were assessed by multicolor flow cytometry. The following ICM were measured by flow cytometry: PD1, CTLA4, BTLA, CD137, CD27, GITR, OX40, LAG3 and TIM3. Dynamics of ICM expression were assessed using nonparametric paired samples tests. Significant changes were noted for PD1, BTLA and CD27 on multiple IC types during or after radiotherapy. Nonsignificant trends for increased expression of OX40 and GITR from baseline until the end of RT were observed on CD4 T cells and CD4+ CD39+ T cells. In patients with samples at recurrence of disease, a nonsignificant increase of TIM3 and LAG3 positive CD4+ CD39+ T cells was evident, accompanied by an increase of double positive cells for TIM3/LAG3. Potential future targets to be combined with RT in the conventional treatment and anti-PD1/PD-L could be BTLA agonists, or agonistic antibodies to costimulatory ICM like CD137, OX40 or GITR. The combination of cetuximab with CD27 agonistic antibodies enhancing ADCC or the targeting of TIM3/LAG3 may be another promising strategy