bluuebunny/crossref_metadata_2025 huggingface dataset:
5‐Aminolevulinic acid/sodium ferrous citrate enhanced the antitumor effects of programmed cell death‐ligand 1 blockade by regulation of exhausted T cell metabolism in a melanoma model
Authors: Hu Xin , Que Weitao , Hirano Hiroshi , Wang Zhidan , Nozawa Naoko , Ishii Takuya , Ishizuka Masahiro , Ito Hidenori , Takahashi Kiwamu , Nakajima Motowo , Tanaka Tohru , Zhu Ping , Guo Wen‐Zhi , Li Xiao‐Kang
Published: May 2021

Mitochondria are key cytoplasmic organelles. Their activation is critical for the generation of T cell proliferation and cytotoxicity. Exhausted tumor‐infiltrating T cells show a decreased mitochondrial function and mass. 5‐Aminolevulinic acid (5‐ALA), a natural amino acid that is only produced in the mitochondria, has been shown to influence metabolic functions. We hypothesized that 5‐ALA with sodium ferrous citrate (SFC) might provide metabolic support for tumor‐infiltrating T cells. In a mouse melanoma model, we found that 5‐ALA/SFC with a programmed cell death‐ligand 1 (PD‐L1) blocking Ab synergized tumor regression. After treatment with 5‐ALA/SFC and anti‐PD‐L1 Ab, tumor infiltrating lymphocytes (TILs) were not only competent for the production of cytolytic particles and cytokines (granzyme B, interleukin‐2, and γ‐interferon) but also showed enhanced Ki‐67 activity (a proliferation marker). The number of activated T cells (PD‐1+Tim‐3−) was also significantly increased. Furthermore, we found that 5‐ALA/SFC activated the mitochondrial functions, including the oxygen consumption rate, ATP level, and complex V expression. The mRNA levels of Nrf‐2, HO‐1, Sirt‐1, and PGC‐1α and the protein levels of Sirt‐1 were upregulated by treatment with 5‐ALA/SFC. Taken together, our findings revealed that 5‐ALA/SFC could be a key metabolic regulator in exhausted T cell metabolism and suggested that 5‐ALA/SFC might synergize with anti‐PD‐1/PD‐L1 therapy to boost the intratumoral efficacy of tumor‐specific T cells. Our study not only revealed a new aspect of immune metabolism, but also paved the way to develop a strategy for combined anti‐PD‐1/PD‐L1 cancer immunotherapy.
Clonal evidence for the development of neuroblastoma with extensive copy‐neutral loss of heterozygosity arising in a mature teratoma
Authors: Ono Rintaro , Ueno Hiroo , Yoshida Kenichi , Takahashi Satoko , Yoshihara Hiroki , Nozaki Taiki , Suzuki Koyu , Nakazawa Atsuko , Saiki Ryunosuke , Seki Masafumi , Takita Junko , Ogawa Seishi , Manabe Atsushi , Hasegawa Daisuke
Published: May 2021

Mature teratomas are usually benign tumors that rarely undergo malignant transformation. We report an advanced neuroblastoma arising in a mature teratoma of the ovary. Whole‐exome sequencing identified extensive copy‐neutral loss of heterozygosity (LOH) in both neuroblastoma and teratoma elements, suggesting that the neuroblastoma evolved from the teratoma. In addition, several truncating germline heterozygous variants in tumor suppressor genes, including RBL2 and FBXW12, became homozygous as a result of LOH. Collectively, we speculate that extensive LOH in teratoma cells may force heterozygous germline variants to become homozygous, which, in turn, may contribute to the development of neuroblastoma with the acquisition of additional chromosomal changes.
Casp8 acts through A20 to inhibit PD‐L1 expression: The mechanism and its implication in immunotherapy
Authors: Zou Jiahuan , Xia Hongwei , Zhang Chenliang , Xu Huanji , Tang Qiulin , Zhu Gongmin , Li Jielang , Bi Feng
Published: May 2021

Immunotherapy targeting the PD‐L1/PD‐1 pathway is a novel type of clinical cancer treatment, but only small subsets of patients can benefit from it because of multiple factors. PD‐L1/PD‐1 expression is a biomarker for predicting the efficacy of anti‐PD‐L1/PD‐1 therapy, which highlights the importance of understanding the regulatory mechanisms of PD‐L1 expression in cancer cells. Casp8 is an apical caspase protease involved in mediating cell apoptosis, but it also has multiple nonapoptotic functions. Casp8 mutations are associated with increased risks of cancer, and low expression of Casp8 is closely connected with poor prognosis in patients with cancer. In addition, mutations of Casp8 in lymphocytes also lead to human immunodeficiency, thereby causing dysfunction of the innate immune system, but the roles of Casp8 in antitumor immunity remain unclear. Here, we found that knocking down Casp8 in mouse melanoma cells promoted tumor progression in an immune system–dependent manner. Mechanistically, Casp8 induced PD‐L1 degradation by upregulating TNFAIP3 (A20) expression, a ubiquitin‐editing enzyme that results in PD‐L1 ubiquitination. In addition, compared with Casp8fl/fl mice, mice with conditional deletion of Casp8 in natural killer (NK) cells (Ncr1iCre/+Casp8fl/fl mice) showed a decreased frequency of IFN‐γ+ and CD107a+ NK cells but an increased frequency of PD‐1+ and CTLA‐4+ NK cells. Melanoma cells with Casp8 knocked down exhibited sensitivity to anti‐PD‐1 or anti‐CTLA‐4 antibody treatments, particularly in Ncr1iCre/+Casp8fl/fl mice. Together, the results indicate that Casp8 induces PD‐L1 degradation by upregulating A20 expression and that decreased Casp8 expression is a potential biomarker for predicting the sensitivity to anti‐PD‐L1/PD‐1 immunotherapy.
Serum and urine free light chains measurements in patients with systemic sclerosis: novel biomarkers for disease activity
Authors: Gigante Antonietta , Pellicano Chiara , Leodori Giorgia , Napodano Cecilia , Vantaggio Lorenzo , Gulli Francesca , Marino Mariapaola , Visentini Marcella , Rosato Edoardo , Basile Umberto
Published: May 2021

Circulating free light chains (FLCs), considered biomarkers of B cell activity, are frequently elevated in patients affected by systemic inflammatory autoimmune diseases. As the systemic sclerosis (SSc) clinical course can be variable, this study is aimed at evaluating FLCs levels in affected individuals as biomarkers of disease activity. We assessed FLC levels in serum and urine of 72 SSc patients and 30 healthy controls (HC). Results were analyzed in comparison with overall clinical and laboratory findings, disease activity index (DAI) and disease severity scale (DSS). SSc patients displayed increased levels of κ and λ FLC in serum significantly higher than HC (p = 0.0001) alongside the mean values of free κ/λ ratio and κ + λ sum (p = 0.0001). SSc patients showed increased free κ in urine with a κ/λ higher than HC (p = 0.0001). SSc patients with increased κ + λ in serum showed that erythro-sedimentation rate (p = 0.034), C-reactive protein (p = 0.003), DAI (p = 0.024) and DSS (p = 0.015) were higher if compared to SSc patients with normal levels of FLC. A positive linear correlation was found between serum levels of free κ and DAI (r = 0.29, p = 0.014). In addition, SSc patients with increased free κ in urine had higher DAI (p = 0.048) than SSc patients with normal κ levels. Our results strengthen the role of serum FLC as useful biomarker in clinical practice to early diagnosis and monitor disease activity, showing for the first time that also urine FLC levels correlated with disease activity in SSc patients.
Increased interdigitation zone visibility on optical coherence tomography following systemic fibroblast growth factor receptor 1‐3 tyrosine kinase inhibitor anticancer therapy
Authors: Charng Jason , Attia Mary S. , Arunachalam Sukanya , Lam Wei‐Sen , Creaney Jenette , Muruganandan Sanjeevan , Read Catherine , Millward Michael , Spiro Jon , Chakera Aron , Lee Y. C. Gary , Nowak Anna K. , Chen Fred K.
Published: May 2021

Background

To describe ocular adverse events and retinal changes during fibroblast growth factor receptor (FGFR) inhibitor (AZD4547) anticancer therapy.

Methods

This is a sub‐study examining ocular adverse effects from AZD4547 therapy (single‐centre, open‐label, single arm phase II clinical trial). Comprehensive ocular examinations were performed 3 weekly in 24 patients. Macular optical coherence tomography (OCT) scan (300 × 250) was obtained at each visit and OCT parameters [central 1 mm retinal thickness (CRT) and total macular volume in central 6 mm] extracted. OCT scans were subdivided into outer (ELM to RPE) and inner (ELM to ILM) layers to compare outer and inner retinal changes.

Results

In 24 patients, AZD4547 was associated with eyelash elongation (n = 5, 21%) and punctate corneal erosion (n = 2, 8%). One patient developed clinically significant posterior capsular opacification during the study. OCT data were available in 23 patients, retinal changes ranged from an asymptomatic increased visibility of the interdigitation zone (IDZ) (n = 10, 43%) to multilobular subretinal fluid pockets (n = 5, 22%), which was associated with mild visual acuity loss. In a subset of patients (n = 9) with pre‐AZD4547 dosing OCT baseline, CRT increased by mean (SD) of 9 (4) μm in those with IDZ change only compared with 64 (38) μm in those with other retinal changes. Retinal changes tended to be bilateral, self‐limiting and improved over time without medical intervention.

Conclusions

The ocular signs and symptoms did not result in dose cessation. Posteriorly, FGFR inhibition leads to outer retinal changes ranging from increased visibility of IDZ to distinct, multiple fluid pockets.
Characteristics, natural evolution and surgical treatment outcomes of unilateral laryngeal paralysis versus ankylosis: A longitudinal cohort study
Authors: Lisan Quentin , Couineau Florent , Laccourreye Ollivier
Published: May 2021

Aims

Although unilateral laryngeal immobility (ULI) can results from paralysis or ankylosis of the cricoarytenoid joint, no comparative study exists to date. Aim of this study was to compare clinical features, aetiologies, spontaneous recovery and evolution after surgical treatment of ULI according to its mechanism.

Methodology

Longitudinal observational cohort study between 1992 and 2017 in a tertiary care referral centre and university teaching hospital. All adult patients with isolated ULI were included. Presenting symptoms and demographic data were recorded at baseline. During follow‐up, natural recovery and, if a surgical treatment was performed, treatment failure rate were noted.

Results

994 patients were included, 56.4% of male and with a mean age of 58 years. Overall, 91% had paralysis and 9% had ankylosis. Dysphonia was the main symptom in both groups (>96%). Dyspnoea was more frequent in patients with ankylosis (26.1% vs 4.2% in those with paralysis) whereas dysphagia was more frequent in those with paralysis (31.1% vs 20% in those with ankylosis). With a mean follow‐up of 2.3 years (±5.1), spontaneous recovery did not differ according to ULI’s aetiology (hazard ratio 1.43, 95% confidence interval 0.85‐2.40). Overall, 37.1% underwent a surgical treatment, and paralysis was associated with a lower odd of treatment failure (hazard ratio 0.27, 95% confidence interval 0.10‐0.70) over a mean follow‐up of 3.1 years (±4.1).

Conclusion

ULI resulting from paralysis or ankylosis differ in their symptoms and responses to surgical treatment, whereas natural evolution was similar.
Patterns of positive patch test reactions to formaldehyde and formaldehyde releasers at the Finnish Institute of Occupational Health from 2007 to 2020
Authors: Aalto‐Korte Kristiina , Pesonen Maria
Published: May 2021

Background

Formaldehyde is an important contact sensitizer. Formaldehyde releasing substances induce positive reactions in formaldehyde‐allergic patients, but there are also reactions independent of formaldehyde allergy. In an earlier study, stronger formaldehyde reactions led to more positive reactions to quaternium‐15.

Objectives

To analyze patterns of positive patch test reactions to formaldehyde and different formaldehyde releasers.

Methods

Patch test files of 1497 patients investigated during the period November 2007–August 2020 were retrospectively reviewed for positive reactions to formaldehyde and its releasers. During the study period, almost all (≥99.3%) patients were tested with a formaldehyde dilution series and six formaldehyde releasers.

Results

Ninety‐three patients tested positive to formaldehyde; 80% of these had positive reactions to at least one formaldehyde releaser, most often benzylhemiformal. There were only nine independent contact allergies to formaldehyde releasers. There were only two reactions to 2‐bromo‐2‐nitropropane‐1,3‐diol and they occurred in formaldehyde‐negative patients. In patients with extreme (+++) reactions to formaldehyde, concomitant positive reactions to any of the other 11 investigated formaldehyde releasers were more common than in patients with milder formaldehyde reactions.

Conclusions

Strong formaldehyde reactions were associated with positive reactions to formaldehyde releasers.
Complete mesocolic excision versus conventional surgery for colon cancer: A systematic review and meta‐analysis
Authors: Crane Jasmine , Hamed Mazin , Borucki Joseph P. , El‐Hadi Ahmed , Shaikh Irshad , Stearns Adam T
Published: May 2021

Aim

Complete mesocolic excision (CME) lacks consistent data advocating operative superiority compared to conventional surgery for colon cancer. We performed a systematic review and meta‐analysis, analysing population characteristics and perioperative, pathological and oncological outcomes.

Methods

D3 extended lymphadenectomy dissection was considered comparable to CME, and D2 and D1 dissection to be comparable to conventional surgery. Outcomes reviewed included lymph node yield, R1 resection, overall complications, overall survival and disease‐free survival.

Results

In all, 3039 citations were identified; 148 studies underwent full‐text reviews and 31 matched inclusion criteria: total cohort 26 640 patients (13 830 CME/D3 vs. 12 810 conventional). Overall 3‐ and 5‐year survival was higher in the CME/D3 group compared with conventional surgery: relative risk (RR) 0.69 (95% CI 0.51–0.93, P = 0.016) and RR 0.78 (95% CI 0.64–0.95, P = 0.011) respectively. Five‐year disease‐free survival also demonstrated CME/D3 superiority (RR 0.67, 95% CI 0.52–0.86, P < 0.001), with similar findings at 1 and 3 years. There were no statistically significant differences between the CME/D3 and conventional group in overall complications (RR 1.06, 95% CI 0.97–1.14, P = 0.483) or anastomotic leak (RR 1.02, 95% CI 0.81–1.29, P = 0.647).

Conclusions

Meta‐analysis suggests CME/D3 may have a better overall and disease‐free survival compared to conventional surgery, with no difference in perioperative complications. Quality of evidence regarding survival is low, and randomized control trials are required to strengthen the evidence base.
The identification of biophysical parameters which reflect skin status following mechanical and chemical insults
Authors: Jayabal Hemalatha , Bates‐Jensen Barbara M. , Abiakam Nkemjika S. , Worsley Peter R. , Bader Dan L.
Published: May 2021

Background

Skin is constantly exposed to mechanical and chemical insults, in the form of prolonged loading, overhydration or exposure to irritants. An array of non‐invasive biophysical tools has been adopted to monitor the changes in skin response. The present study aims to identify a set of robust parameters sensitive to mechanical and chemical challenges to skin integrity.

Materials and methods

Eleven healthy participants were recruited to evaluate the skin response following mechanical loading, tape stripping, overhydration and chemical irritation. Forearm skin responses were recorded at baseline and at three time points following the insult. Measurements included transepidermal water loss, sub‐epidermal moisture, erythema and laser Doppler imaging. Thresholds were informed by basal values, and the sensitivity of parameters to detect skin changes was evaluated.

Results

High degree of variability in skin response was observed with selected biophysical parameters, such as sub‐epidermal moisture, laser Doppler imaging and erythema, even in the absence of an applied insult. Temporal skin response revealed distinct response profiles during each evoked insult. Indeed, the sensitivity of the biophysical parameters was influenced by the threshold values and time point of measurement. Some statistically significant correlations were determined between the biophysical parameters.

Conclusion

The study revealed that thresholds derived from single biophysical parameters were limited in detecting skin changes following insults. A complementary evaluation using combined parameters has the potential to provide a more sensitive assessment. Further research is required to identify robust biophysical parameters, to aid the early detection of skin damage in clinical settings.
Dexmedetomidine combined with midazolam infusion guided by bispectral index during bronchoscopy
Authors: Zhang Qiudi , Zhou Jun , He Qian , Guan Shuhong , Qiu Hui , Xu Xiong , Xu Qianqian , Dai Pei , Dong Dingjiao , Wang Xuemin , Zhang Sujuan
Published: May 2021

Background

Conscious sedation guided by bispectral index (BIS) during bronchoscopy has been proved to be a feasible approach. This study aimed to investigate the safety and efficacy of dexmedetomidine combined with midazolam for undergoing conscious sedation during bronchoscopy.

Methods

The trial was registered prior to patient enrollment at the Chinese Clinical Trial Registry. Patients were randomized into DEX group (dexmedetomidine combined with midazolam) and FEN group (fentanyl combined with midazolam). Bronchoscopy was performed under awake sedation titrated to a BIS level of 60–80. The primary endpoint was the incidence of hypoxia, the secondary endpoint was the incidence of bradycardia and hypotension, effect of sedation including satisfaction degree (VAS) of the operators and patients and patients’ willingness to undergo bronchoscopy again.

Results

A total of 222 cases in DEX group and 211 cases in FEN group completed the study. The incidence of hypoxia and tachycardia in DEX group was lower than that in FEN group (8.1% vs 14.7%, 10.4% vs 19.0%,p < 0.05), and the incidence of hypotension and bradycardia in DEX group was higher than that in FEN group (6.8% vs 0, 15.3% vs 8.1%,p < 0.05). Midazolam dosage was significantly lower in the DEX group than in the FEN group, and the duration of surgery was significantly longer in the DEX group. The differences in intraoperative discomfort of VAS score, satisfaction VAS score, and willingness rate to undergo bronchoscopy again were not statistically significant between the two groups. In addition, the proportion of “procedural interference by patient movement” in DEX group was higher than that in FEN group.

Conclusions

The conscious sedation regimen of dexmedetomidine combined with midazolam monitored by BIS is considered to be safe and effective during bronchoscopy. The occurrence of hypoxia and tachycardia was less, and the fluctuation of blood pressure and heart rate was mild, but the proportion of bradycardia in dexmedetomidine group was higher than that in fentanyl combined with midazolam group.
A randomized, double‐blind, placebo‐ and positive‐controlled crossover study of the effects of durlobactam on cardiac repolarization in healthy subjects
Authors: O’Donnell John , Maloney Kathleen , Steidler Melissa , Morrison Royce , Isaacs Robin
Published: May 2021

Durlobactam (formerly ETX2514) is a diazabicyclooctane β‐lactamase inhibitor that inhibits class A, C, and D β‐lactamases. Sulbactam combined with durlobactam has in vitro and in vivo activity against Acinetobacter baumannii including carbapenem‐ and colistin‐resistant isolates and is being developed for treating serious infections due to A. baumannii. The effect of a single supratherapeutic dose of durlobactam on the heart rate corrected QT interval (QTc) was evaluated in healthy subjects in a placebo‐ and active‐controlled, single‐infusion, three‐way crossover study. Subjects were randomized to 1 of 6 sequences that included a single 3‐h i.v. infusion of durlobactam 4 g (supratherapeutic dose), a single 3‐h i.v. infusion of placebo, and a single 3‐h i.v. infusion of placebo plus a single oral dose of moxifloxacin 400 mg given open‐label at the end of the i.v. infusion. In each treatment period, Holter electrocardiogram (ECG) measurements were obtained from predose through 24 h post‐start of infusion. For the primary ECG end point, placebo‐corrected change‐from‐baseline corrected QT Fridericia’s formula (ΔΔQTcF), no significant change was observed with durlobactam. A concentration‐QT analysis demonstrated no significant effect of durlobactam on ECG parameters, including QT interval prolongation. Thus, durlobactam has a low risk for prolonging the QT interval and is unlikely to produce any proarrhythmic effects.
Preoperative medication use and development of postoperative delirium and cognitive dysfunction
Authors: Heinrich Maria , Nottbrock Anja , Borchers Friedrich , Mörgeli Rudolf , Kruppa Jochen , Winterer Georg , Slooter Arjen J. C. , Spies Claudia ,   the BioCog Consortium
Published: May 2021

Postoperative delirium (POD) and postoperative (neuro‐)cognitive disorder (POCD) are frequent and serious complications after operations. We aim to investigate the association between pre‐operative polypharmacy and potentially inappropriate medications and the development of POD/POCD in elderly patients. This investigation is part of the European BioCog project (www.biocog.eu), a prospective multicenter observational study with elderly surgical patients. Patients with a Mini‐Mental State Examination score less than or equal to 23 points were excluded. POD was assessed up to 7 days after surgery using the Nursing Delirium Screening Scale, Confusion Assessment Method (for the intensive care unit [ICU]), and a patient chart review. POCD was assessed 3 months after surgery with a neuropsychological test battery. Pre‐operative long‐term medication was evaluated in terms of polypharmacy (≥5 agents) and potentially inappropriate medication (defined by the PRISCUS and European list of potentially inappropriate medications [EU(7)‐PIM] lists), and associations with POD and POCD were analyzed using logistic regression analysis. Eight hundred thirty‐seven participants were included for analysis of POD and 562 participants for POCD. Of these, 165 patients (19.7%) fulfilled the criteria of POD and 60 (10.7%) for POCD. After adjusting for confounders, pre‐operative polypharmacy and intake of potentially inappropriate medications could not be shown to be associated with the development of POD nor POCD. We found no associations between pre‐operative polypharmacy and potentially inappropriate medications and development of POD and POCD. Future studies should focus on the evaluation of drug interactions to determine whether patients benefit from a pre‐operative adjustment.
Immunohistochemical expression of PAX8, PAX2, and cytokeratin in melanomas
Authors: Plotzke Jaclyn M. , Zhao Raymond , Hrycaj Steven M. , Harms Paul W. , Mehra Rohit , Chan May P.
Published: May 2021

Background

Deviations from the classic melanocytic immunophenotype in melanoma can present a diagnostic challenge. PAX8 and PAX2 are common markers for renal or Müllerian differentiation. While most PAX8+ or PAX2+ carcinomas are seldom confused with melanoma, some cases may show a more ambiguous immunophenotype, especially when MiTF family altered renal cell carcinoma (MiTF‐RCC) is in the differential diagnosis. Neither PAX8 nor PAX2 expression has been reported in melanoma to date. We aimed to better characterize PAX8, PAX2, and cytokeratin immunoreactivity in a large series of melanomas.

Methods

Tissue microarrays consisting of 263 melanomas were immunostained for PAX8, PAX2, and cytokeratin and graded by an h‐score.

Results

PAX8 expression was seen in 7.9% of melanomas and was significantly associated with spindle cytomorphology. PAX2 was positive in one (0.4%) melanoma. Cytokeratin positivity was seen in three (1.2%) cases and was associated with metastases.

Conclusions

PAX8 is expressed in a subset of melanomas and may be strong/extensive. As PAX8 positivity does not exclude a diagnosis of melanoma, it should be used in conjunction with other immunohistochemical markers, such as cytokeratin and PAX2, when melanoma, MiTF‐RCC, and other PAX8+ tumors are in the differential diagnosis.
Does Ignorance of Economic Returns and Costs Explain the Educational Aspiration Gap? Representative Evidence from Adults and Adolescents
Authors: Lergetporer Philipp , Werner Katharina , Woessmann Ludger
Published: May 2021

The gap in university enrolment by parental education is large and persistent in many countries. In our representative survey of German adults, 74% of university graduates, but only 36% of those without a university degree, favour university education for their children. The latter are more likely to underestimate returns and overestimate costs of university. Similarly, 75% of adolescents with university‐educated parents, but only 51% without university‐educated parents aspire to a university degree. Experimental provision of general return and cost information does not close the aspiration gap as treatment effects are at least as strong for individuals with a university background as for those without. Differences in economic preference parameters also cannot account for the educational aspiration gap.
Fecal microbiota transfer for refractory intestinal graft‐versus‐host disease — Experience from two German tertiary centers
Authors: Goeser Felix , Sifft Barbara , Stein‐Thoeringer Christoph , Farowski Fedja , Strassburg Christian P. , Brossart Peter , Higgins Paul G. , Scheid Christoph , Wolf Dominik , Holderried Tobias A. W. , Vehreschild Maria J. G. T. , Cruz Aguilar Marta Rebeca
Published: May 2021

Rationale

Steroid refractory graft‐vs‐host disease (sr‐GvHD) represents a challenging complication after allogeneic hematopoietic cell transplantation (allo‐HCT). Intestinal microbiota (IM) diversity and dysbiosis were identified as influencing factors for the development of acute GvHD. Fecal microbiota transfer (FMT) is hypothesized to restore IM dysbiosis, but there is limited knowledge about the significance of FMT in the treatment of sr‐GvHD.

Objectives

We studied the effects of FMT on sr‐GvHD in allo‐HCT patients from two German tertiary clinical centers (n = 11 patients; period: March 2017 until July 2019). To assess safety and clinical efficacy, we analyzed clinical data pre‐ and post‐FMT (day ‐14 to +30 relative to FMT). Moreover, IM were analyzed in donor samples and in a subset of patients pre‐ and post‐FMT by 16S rRNA sequencing.

Results

Post‐FMT, we observed no intervention‐associated, systemic inflammatory responses and only minor side effects (5/11 patients: abdominal pain and transformation of peristalsis—each 3/11 and vomiting—1/11). Stool frequencies and volumes were significantly reduced [pre‐ vs post‐FMT (d14): P < .05, respectively] as well as clear attenuation regarding both grading and staging of sr‐GvHD was present upon FMT. Moreover, IM analyses revealed an increase of alpha diversity as well as a compositional shifts toward the donor post‐FMT.

Conclusions

In our study, we observed positive effects on sr‐GVHD after FMT without the occurrence of major adverse events. Although these findings are in line with published data on beneficial effects of FMT in sr‐GvHD, further randomized clinical studies are urgently needed to better define the clinical validity including mode of action.
Peripheral taste detection in honey bees: What do taste receptors respond to?
Authors: Bestea Louise , Réjaud Alexandre , Sandoz Jean‐Christophe , Carcaud Julie , Giurfa Martin , de Brito Sanchez Maria Gabriela
Published: May 2021

Understanding the neural principles governing taste perception in species that bear economic importance or serve as research models for other sensory modalities constitutes a strategic goal. Such is the case of the honey bee (Apis mellifera), which is environmentally and socioeconomically important, given its crucial role as pollinator agent in agricultural landscapes and which has served as a traditional model for visual and olfactory neurosciences and for research on communication, navigation, and learning and memory. Here we review the current knowledge on honey bee gustatory receptors to provide an integrative view of peripheral taste detection in this insect, highlighting specificities and commonalities with other insect species. We describe behavioral and electrophysiological responses to several tastant categories and relate these responses, whenever possible, to known molecular receptor mechanisms. Overall, we adopted an evolutionary and comparative perspective to understand the neural principles of honey bee taste and define key questions that should be answered in future gustatory research centered on this insect.
A functional variant of the long noncoding RNA AL110200 is associated with the risk of ischaemic stroke recurrence
Authors: Song Li , Li Hao , Suo Miaomiao , Sun Yingying , Su Ming , Song Yan , Xiao Ning , Hui Rutai , Qin Chunchang , Chen Jingzhou
Published: May 2021

Background and purpose

This study aimed to test the hypothesis that long noncoding RNA (lncRNA) AL110200 exerts a proinflammatory effect on atherosclerosis and that the variant rs901681 contributes to ischaemic stroke incidence and recurrence.

Methods

The expression of AL110200 was analyzed in THP‐1 cells treated with oxidized low‐density lipoprotein and in human peripheral blood in a coronary heart disease and control population to determine the role of AL110200 in atherosclerosis. The effect of AL110200 on cell adhesion and invasion was tested. The plasma level of leukotriene B4 and rs901681 genotype distribution were assessed in 220 participants. In 1004 ischaemic stroke patients and 1434 controls, the association between rs901681 and stroke incidence was analyzed by logistic regression, and the association of rs901681 and stroke prognosis was analyzed using Kaplan–Meier analysis and the Cox proportional hazards model.

Results

Increased expression of AL110200 was observed in THP‐1 cells under oxidized low‐density lipoprotein treatment. Knockdown of AL110200 reduced the adhesive and invasive ability of THP‐1 cells. AL110200 expression in peripheral blood was significantly higher in the coronary heart disease group than in the controls. The GG genotype of rs901681 is associated with reduced plasma leukotriene B4. In the ischaemic stroke population, rs901681 was not associated with ischaemic stroke incidence (p = 0.686). Patients carrying rs901681 GG had a lower risk for stroke recurrence at age ≥60 years (p = 0.001), cardiovascular stroke death (p = 0.022) and all‐cause mortality (p = 0.034) in the all‐age group.

Conclusions

AL110200 might exert a proinflammatory effect on atherosclerosis, and the variant rs901681 might be a strong predictor of stroke prognosis in ischaemic stroke patients.
Quantitative magnetic resonance imaging of the brachial plexus shows specific changes in nerve architecture in chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy and motor neuron disease
Authors: van Rosmalen Marieke H. J. , Goedee H. Stephan , Derks Rosina , Asselman Fay‐Lynn , Verhamme Camiel , de Luca Alberto , Hendrikse J. , van der Pol W. Ludo , Froeling Martijn
Published: May 2021

Background

The immunological pathophysiologies of chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) differ considerably, but neither has been elucidated completely. Quantitative magnetic resonance imaging (MRI) techniques such as diffusion tensor imaging, T2 mapping, and fat fraction analysis may indicate in vivo pathophysiological changes in nerve architecture. Our study aimed to systematically study nerve architecture of the brachial plexus in patients with CIDP, MMN, motor neuron disease (MND) and healthy controls using these quantitative MRI techniques.

Methods

We enrolled patients with CIDP (n = 47), MMN (n = 29), MND (n = 40) and healthy controls (n = 10). All patients underwent MRI of the brachial plexus and we obtained diffusion parameters, T2 relaxation times and fat fraction using an automated processing pipeline. We compared these parameters between groups using a univariate general linear model.

Results

Fractional anisotropy was lower in patients with CIDP compared to healthy controls (p < 0.001), patients with MND (p = 0.010) and MMN (p < 0.001). Radial diffusivity was higher in patients with CIDP compared to healthy controls (p = 0.015) and patients with MND (p = 0.001) and MMN (p < 0.001). T2 relaxation time was elevated in patients with CIDP compared to patients with MND (p = 0.023). Fat fraction was lower in patients with CIDP and MMN compared to patients with MND (both p < 0.001).

Conclusion

Our results show that quantitative MRI parameters differ between CIDP, MMN and MND, which may reflect differences in underlying pathophysiological mechanisms.
The impact of management controls on public managers’ well‐being
Authors: Siverbo Sven
Published: May 2021

Public sector managers are increasingly subject to management controls. In this study, we determine how management controls in public sector organizations influence managers’ well‐being at work. Based on central beliefs and concepts in the management control literature and self‐determination theory, we develop, test, and confirm a theoretical model predicting that positive effects of management controls on public managers’ well‐being are explained by increased role clarity and negative effects by increased control burden, which in turn affects managers’ self‐determination. The model was tested through web survey responses from 1,029 managers from ten Swedish local government organizations. Our research contributes to the literature on well‐being effects of management controls by specifying how positive and negative effects on managers’ well‐being occur.
Autophagy at the interface of endothelial cell homeostasis and vascular disease
Authors: Mameli Eleonora , Martello Andrea , Caporali Andrea
Published: May 2021

Autophagy is an essential intracellular process for cellular quality control. It enables cell homeostasis through the selective degradation of harmful protein aggregates and damaged organelles. Autophagy is essential for recycling nutrients, generating energy to maintain cell viability in most tissues and during adverse conditions such as hypoxia/ischaemia. The progressive understanding of the mechanisms modulating autophagy in the vasculature has recently led numerous studies to link intact autophagic responses with endothelial cell (EC) homeostasis and function. Preserved autophagic flux within the ECs has an essential role in maintaining their physiological characteristics, whereas defective autophagy can promote endothelial pro‐inflammatory and atherogenic phenotype. However, we still lack a good knowledge of the complete molecular repertoire controlling various aspects of endothelial autophagy and how this is associated with vascular diseases. Here, we provide an overview of the current state of the art of autophagy in ECs. We review the discoveries that have so far defined autophagy as an essential mechanism in vascular biology and analyse how autophagy influences ECs behaviour in vascular disease. Finally, we emphasise opportunities for compounds to regulate autophagy in ECs and discuss the challenges of exploiting them to resolve vascular disease.
Recent advances on smart glycoconjugate vaccines in infections and cancer
Authors: Anderluh Marko , Berti Francesco , Bzducha‐Wróbel Anna , Chiodo Fabrizio , Colombo Cinzia , Compostella Federica , Durlik Katarzyna , Ferhati Xhenti , Holmdahl Rikard , Jovanovic Dragana , Kaca Wieslaw , Lay Luigi , Marinovic‐Cincovic Milena , Marradi Marco , Ozil Musa , Polito Laura , Reina Josè Juan , Reis Celso A. , Sackstein Robert , Silipo Alba , Švajger Urban , Vaněk Ondřej , Yamamoto Fumiichiro , Richichi Barbara , van Vliet Sandra J.
Published: May 2021

Vaccination is one of the greatest achievements in biomedical research preventing death and morbidity in many infectious diseases through the induction of pathogen‐specific humoral and cellular immune responses. Currently, no effective vaccines are available for pathogens with a highly variable antigenic load, such as the human immunodeficiency virus or to induce cellular T‐cell immunity in the fight against cancer. The recent SARS‐CoV‐2 outbreak has reinforced the relevance of designing smart therapeutic vaccine modalities to ensure public health. Indeed, academic and private companies have ongoing joint efforts to develop novel vaccine prototypes for this virus. Many pathogens are covered by a dense glycan‐coat, which form an attractive target for vaccine development. Moreover, many tumor types are characterized by altered glycosylation profiles that are known as “tumor‐associated carbohydrate antigens”. Unfortunately, glycans do not provoke a vigorous immune response and generally serve as T‐cell‐independent antigens, not eliciting protective immunoglobulin G responses nor inducing immunological memory. A close and continuous crosstalk between glycochemists and glycoimmunologists is essential for the successful development of efficient immune modulators. It is clear that this is a key point for the discovery of novel approaches, which could significantly improve our understanding of the immune system. In this review, we discuss the latest advancements in development of vaccines against glycan epitopes to gain selective immune responses and to provide an overview on the role of different immunogenic constructs in improving glycovaccine efficacy.
Influences of pH and substrate supply on the ratio of iron to sulfate reduction
Authors: Paper Janet M. , Flynn Theodore M. , Boyanov Maxim I. , Kemner Kenneth M. , Haller Ben R. , Crank Kathleen , Lower AnneMarie , Jin Qusheng , Kirk Matthew F.
Published: May 2021

Iron reduction and sulfate reduction often occur simultaneously in anoxic systems, and where that is the case, the molar ratio between the reactions (i.e., Fe/SO42− reduced) influences their impact on water quality and carbon storage. Previous research has shown that pH and the supply of electron donors and acceptors affect that ratio, but it is unclear how their influences compare and affect one another. This study examines impacts of pH and the supply of acetate, sulfate, and goethite on the ratio of iron to sulfate reduction in semi‐continuous sediment bioreactors. We examined which parameter had the greatest impact on that ratio and whether the parameter influences depended on the state of each other. Results show that pH had a greater influence than acetate supply on the ratio of iron to sulfate reduction, and that the impact of acetate supply on the ratio depended on pH. In acidic reactors (pH 6.0 media), the ratio of iron to sulfate reduction decreased from 3:1 to 2:1 as acetate supply increased (0–1 mM). In alkaline reactors (pH 7.5 media), iron and sulfate were reduced in equal proportions, regardless of acetate supply. Secondly, a comparison of experiments with and without sulfate shows that the extent of iron reduction was greater if sulfate reduction was occurring and that the effect was larger in alkaline reactors than acidic reactors. Thus, the influence of sulfate supply on iron reduction extent also depended on pH and suggests that iron reduction grows more dependent on sulfate reduction as pH increases. Our results compare well to trends in groundwater geochemistry and provide further evidence that pH is a major control on iron and sulfate reduction in systems with crystalline (oxyhydr)oxides. pH not only affects the ratio between the reactions but also the influences of other parameters on that ratio.
Interannual variation in rainfall modulates temperature sensitivity of carbon allocation and flux in a tropical montane wet forest
Authors: Lyu Maokui , Giardina Christian P. , Litton Creighton M.
Published: May 2021

Tropical forests exert a disproportionately large influence on terrestrial carbon (C) balance but projecting the effects of climate change on C cycling in tropical forests remains uncertain. Reducing this uncertainty requires improved quantification of the independent and interactive effects of variable and changing temperature and precipitation regimes on C inputs to, cycling within and loss from tropical forests. Here, we quantified aboveground litterfall and soil‐surface CO2 efflux (“soil respiration”; FS) in nine plots organized across a highly constrained 5.2°C mean annual temperature (MAT) gradient in tropical montane wet forest. We used five consecutive years of these measurements, during which annual rainfall (AR) steadily increased, in order to: (a) estimate total belowground C flux (TBCF); (b) examine how interannual variation in AR alters the apparent temperature dependency (Q10) of above‐ and belowground C fluxes; and (c) quantify stand‐level C allocation responses to MAT and AR. Averaged across all years, FS, litterfall, and TBCF increased positively and linearly with MAT, which accounted for 49, 47, and 46% of flux rate variation, respectively. Rising AR lowered TBCF and FS, but increased litterfall, with patterns representing interacting responses to declining light. The Q10 of FS, litterfall, and TBCF all decreased with increasing AR, with peak sensitivity to MAT in the driest year and lowest sensitivity in the wettest. These findings support the conclusion that for this tropical montane wet forest, variations in light, water, and nutrient availability interact to strongly influence productivity (litterfall+TBCF), the sensitivity of above‐ and belowground C fluxes to rising MAT (Q10 of FS, litterfall, and TBCF), and C allocation patterns (TBCF:[litterfall+TBCF]).
Spatial biases of information influence global estimates of soil respiration: How can we improve global predictions?
Authors: Stell Emma , Warner Daniel , Jian Jinshi , Bond‐Lamberty Ben , Vargas Rodrigo
Published: May 2021

Soil respiration (Rs), the efflux of CO2 from soils to the atmosphere, is a major component of the terrestrial carbon cycle, but is poorly constrained from regional to global scales. The global soil respiration database (SRDB) is a compilation of in situ Rs observations from around the globe that has been consistently updated with new measurements over the past decade. It is unclear whether the addition of data to new versions has produced better‐constrained global Rs estimates. We compared two versions of the SRDB (v3.0 n = 5173 and v5.0 n = 10,366) to determine how additional data influenced global Rs annual sum, spatial patterns and associated uncertainty (1 km spatial resolution) using a machine learning approach. A quantile regression forest model parameterized using SRDBv3 yielded a global Rs sum of 88.6 Pg C year−1, and associated uncertainty of 29.9 (mean absolute error) and 57.9 (standard deviation) Pg C year−1, whereas parameterization using SRDBv5 yielded 96.5 Pg C year−1 and associated uncertainty of 30.2 (mean average error) and 73.4 (standard deviation) Pg C year−1. Empirically estimated global heterotrophic respiration (Rh) from v3 and v5 were 49.9–50.2 (mean 50.1) and 53.3–53.5 (mean 53.4) Pg C year−1, respectively. SRDBv5’s inclusion of new data from underrepresented regions (e.g., Asia, Africa, South America) resulted in overall higher model uncertainty. The largest differences between models parameterized with different SRDVB versions were in arid/semi‐arid regions. The SRDBv5 is still biased toward northern latitudes and temperate zones, so we tested an optimized global distribution of Rs measurements, which resulted in a global sum of 96.4 ± 21.4 Pg C year−1 with an overall lower model uncertainty. These results support current global estimates of Rs but highlight spatial biases that influence model parameterization and interpretation and provide insights for design of environmental networks to improve global‐scale Rs estimates.
Distinct interaction effects of warming and anthropogenic input on diatoms and dinoflagellates in an urbanized estuarine ecosystem
Authors: Cheung Yan Yin , Cheung Shunyan , Mak Julian , Liu Kailin , Xia Xiaomin , Zhang Xiaodong , Yung Yingkit , Liu Hongbin
Published: May 2021

Diatoms and dinoflagellates are two major bloom‐forming phytoplankton groups in coastal ecosystems and their dominances will notably affect the marine ecosystems. By analyzing an 18‐year monthly monitoring dataset (2000–2017) in the Pearl River Estuary (one of the most highly urbanized and populated estuarine in the world), we observe an increasing trend of the diatom to dinoflagellate ratio (Diatom/Dino). As revealed by multiple statistical models (generalized additive mixed model, random forest, and gradient boosting algorithms), both groups are positively correlated with temperature. Diatoms are positively correlated with nitrate and negatively correlated with ammonium while dinoflagellates show an opposite pattern. The Diatom/Dino trend is explained by an altered nutrient composition caused by a decadal increase in anthropogenic input, at which nitrate increased rapidly while ammonium and phosphate were relatively constant. Regarding the interaction of warming and nutrient dynamics, we observe an additive effect of warming and nitrate enrichment that promotes the increase in diatom cell density, while the dinoflagellate cell density only increases with warming when nutrients are depleted. Our models predict that the Diatom/Dino ratio will further increase with increasing anthropogenic input and global warming in subtropical estuarine ecosystems with nitrate as the dominant inorganic nitrogen; its ecological consequences are worthy of further investigation.
Higher biomass partitioning to absorptive roots improves needle nutrition but does not alleviate stomatal limitation of northern Scots pine
Authors: Zadworny Marcin , Mucha Joanna , Bagniewska‐Zadworna Agnieszka , Żytkowiak Roma , Mąderek Ewa , Danusevičius Darius , Oleksyn Jacek , Wyka Tomasz P. , McCormack M. Luke
Published: May 2021

Harsh environmental conditions affect both leaf structure and root traits. However, shoot growth in high‐latitude systems is predominately under photoperiod control while root growth may occur for as long as thermal conditions are favorable. The different sensitivities of these organs may alter functional relationships above‐ and belowground along environmental gradients. We examined the relationship between absorptive root and foliar traits of Scots pine trees growing in situ along a temperate‐boreal transect and in trees grown in a long‐term common garden at a temperate latitude. We related changes in foliar nitrogen, phosphorus, specific leaf area, needle mass and 13C signatures to geographic trends in absorptive root biomass to better understand patterns of altered tree nutrition and water balance. Increased allocation to absorptive fine roots was associated with greater uptake of soil nutrients and subsequently higher needle nutrient contents in the northern provenances compared with more southern provenances when grown together in a common garden setting. In contrast, the leaf δ13C in northern and southern provenances were similar within the common garden suggesting that higher absorptive root biomass fractions could not adequately increase water supply in warmer climates. These results highlight the importance of allocation within the fine‐root system and its impacts on needle nutrition while also suggesting increasing stomatal limitation of photosynthesis in the context of anticipated climatic changes.