bluuebunny/crossref_metadata_2025 huggingface dataset:
CD4+ T cell counts and soluble programmed death-1 at baseline correlated with hepatitis B surface antigen decline in HIV/HBV coinfection during combined antiretroviral therapy
Authors: Li Xiaodi , Xu Ling , Lu Lianfeng , Liu Xiaosheng , Yang Yang , Wu Yuanni , Han Yang , Li Xiaoxia , Li Yanling , Song Xiaojing , Cao Wei , Li Taisheng
Published: May 2023

Background

Several studies have described the rapid decline and clearance of hepatitis B surface antigen (HBsAg) in human immunodeficiency virus (HIV)/hepatitis B virus (HBV) coinfection after initiating combined antiretroviral therapy (cART). Early decline of HBsAg levels is associated with HBsAg seroclearance in the treatment of chronic HBV infection. This study aims to evaluate the HBsAg kinetics and the determinants of early HBsAg decline in patients with HIV/HBV coinfection during cART.

Methods

A total of 51 patients with HIV/HBV coinfection were enrolled from a previously established HIV/AIDS cohort and followed for a median of 59.5 months after cART initiation. Biochemical tests, virology and immunology assessments were measured longitudinally. The kinetics of HBsAg during cART were analyzed. Soluble programmed death-1 (sPD-1) levels and immune activation markers (CD38 and HLA-DR) were measured at baseline, 1-year and 3-year during treatment. HBsAg response was defined as a decline of more than 0.5 log10 IU/ml at 6 months from the baseline after initiation of cART.

Results

HBsAg declined faster (0.47 log10 IU/mL) in the first six months and attained a decrease of 1.39 log10 IU/mL after 5-year therapy. Seventeen (33.3%) participants achieved a decline of more than 0.5 log10 IU/ml at the first 6 months of cART(HBsAg response) of which five patients achieved HBsAg clearance at a median of 11 months (range: 6-51 months). Multivariate logistic analysis showed the lower baseline CD4+ T cell levels (OR=6.633, P=0.012) and sPD-1 level (OR=5.389, P=0.038) were independently associated with HBsAg response after cART initiation. The alanine aminotransferase abnormality rate and HLA-DR expression were significantly higher in patients who achieved HBsAg response than in those who did not achieve HBsAg response after cART initiation.

Conclusion

Lower CD4 + T cells, sPD-1, and immune activation were related to a rapid HBsAg decline in patients with HIV/HBV-coinfection after the initiation of cART. These findings imply that immune disorders induced by HIV infection may disrupt immune tolerance to HBV, leading to a faster decline in HBsAg levels during coinfection.
Multidisciplinary management of difficult/aggressive growth-hormone pituitary neuro-endocrine tumors
Authors: Bianchi Antonio , Chiloiro Sabrina , Giampietro Antonella , Gaudino Simona , Calandrelli Rosalinda , Mazzarella Ciro , Caldarella Carmelo , Rigante Mario , Gessi Marco , Lauretti Liverana , De Marinis Laura , Olivi Alessandro , Pontecorvi Alfredo , Doglietto Francesco
Published: May 2023

Growth Hormone-secreting adenomas exhibits variable biological behavior and heterogeneous natural history, ranging from small adenomas and mild disease, to invasive and aggressive neoplasms with more severe clinical picture. Patients not cured or controlled after neurosurgical and first-generation somatostatin receptor ligands (SRL) therapy could require multiple surgical, medical and/or radiation treatments to achieve disease control. To date, no clinical, laboratory, histopathological, or neuroradiological markers are able to define the aggressiveness or predict the disease prognosis in patients with acromegaly. Therefore, the management of these patients requires careful evaluation of laboratory assessments, diagnostic criteria, neuroradiology examinations, and neurosurgical approaches to choose an effective and patient-tailored medical therapy. A multidisciplinary approach is particularly useful in difficult/aggressive acromegaly to schedule multimodal treatment, which includes radiation therapy, chemotherapy with temozolomide and other, recent emerging treatments. Herein, we describe the role of the different members of the multidisciplinary team according to our personal experience; a flow-chart for the therapeutic approach of difficult/aggressive acromegaly patients is proposed.
Profiling estrogen, progesterone, and androgen receptors in colorectal cancer in relation to gender, menopausal status, clinical stage, and tumour sidedness
Authors: Refaat Bassem , Aslam Akhmed , Idris Shakir , Almalki Ahmed H. , Alkhaldi Mofareh Y. , Asiri Hassan A. , Almaimani Riyad A. , Mujalli Abdulrahman , Minshawi Faisal , Alamri Sara A. , AlHussain Mona I. , Baltow Badee A. , Alqasmi Mansour H. , Basfar Ghaiyda T. , Alosaimi Ohoud M. , Muhayya Ibrahim A.
Published: May 2023

Background

Although estrogen (ERα/ERβ), progesterone (PGR), and androgen (AR) receptors are pathologically altered in colorectal cancer (CRC), their simultaneous expression within the same cohort of patients was not previously measured.

Methods

ERα/ERβ/PGR/AR proteins were measured in archived paired normal and malignant colon specimens (n =120 patients) by immunohistochemistry, and results were analyzed by gender, age (≤50 vs. ≥60 years), clinical stages (early-stage I/II vs. late-stage III/IV), and anatomical location (right; RSCs vs. left; LSCs). Effects of 17β-estradiol (E2), progesterone (P4), and testosterone alone or combined with the specific blockers of ERα (MPP dihydrochloride), ERβ (PHTPP), PGR (mifepristone), and AR (bicalutamide) on cell cycle and apoptosis were also measured in the SW480 male and HT29 female CRC cell lines.

Results

ERα and AR proteins increased, whilst ERβ and PGR declined markedly in malignant specimens. Moreover, male neoplastic tissues showed highest AR expression, whilst ERβ and PGR weakest alongside ERα strongest expression was seen in cancerous tissues from women aged ≥60 years. Late-stage neoplasms also revealed maximal alterations in the expression of sex steroid receptors. By tumor location, LSCs disclosed significant elevations in ERα with marked declines in PGR compared with RSCs, and ERα strongest alongside PGR weakest expression was detected in advanced LSCs from women aged ≥60 years. Late-stage LSCs from females aged ≥60 years also showed weakest ERβ and strongest AR expression. In contrast, male RSC and LSC tissues exhibited equal ERβ and AR expression in all clinical stages. ERα and AR proteins also correlated positively, whereas ERβ and PGR inversely, with tumor characteristics. Concomitantly, E2 and P4 monotherapies triggered cell cycle arrest and apoptosis in the SW480 and HT29 cells, and while pre-treatment with ERα-blocker enhanced the effects of E2, ERβ-blocker and PGR-blocker suppressed the E2 and P4 anti-cancer actions, respectively. In contrast, treatment with the AR-blocker induced apoptosis, whilst co-treatment with testosterone hindered the effects.

Conclusions

This study advocates that protein expression of sex steroid receptors in malignant tissues could represent prognostic markers, as well as hormonal therapy could provide an alternative strategy against CRC, and their efficacies could be dependent on gender, clinical stage, and tumor location.
Connectivity and fragment size drive plant dispersal and persistence traits in forest steppe fragments
Authors: Szitár Katalin , Tölgyesi Csaba , Deák Balázs , Gallé Róbert , Korányi Dávid , Batáry Péter
Published: May 2023

Introduction

Land use changes have seriously fragmented grasslands leading to extensive biodiversity loss worldwide. Habitat fragmentation affects grasslands at both local and landscape scales, adversely affecting the probability of species colonisation and extinction. In our study, we addressed the effects of fragment size and landscape-scale habitat connectivity on the vegetation composition in two grassland types, i.e., loess steppe fragments (situated on kurgans) and sand steppe fragments of the Pannonian forest steppe region.

Methods

We collected frequency data on vascular plant species in 12 1 m × 1 m quadrats in altogether 60 fragments along a connectivity gradient in sand steppes and loess steppe fragments. We analysed whether habitat specialists, generalists and exotic species were affected by the level of fragmentation based on species richness and traits related to local persistence (life span, clonality and soil seed bank type) and dispersal (dispersal strategy and seed mass) in the two grassland types using linear mixed-effects models.

Results

Based on our results, both fragment size and landscape-scale connectivity were important in shaping the trait composition of the vegetation. We observed more fragmentation effects in generalist than in specialist species. We found that isolation resulted in fewer specialist species with autochorous dispersal strategy in loess steppe fragments, but, at the same time, also fewer exotics. Isolated loess steppe fragments harboured fewer generalist species with persistent seed bank. Large loess steppe fragments supported more wind-dispersed species than smaller ones. In isolated sand steppe fragments, generalists were more frequent with endozoochorous dispersal strategy and without clonal propagation. Life span, clonal propagation and seed mass did not depend on the level of fragmentation in the two grassland types.

Discussion

Our results imply that both sand and loess steppe fragments can rely to some extent on the persistence of clonal perennial specialist and generalist species in small and isolated patches to mitigate fragmentation effects. In conclusion, these processes should be supported by the preservation of large fragments, increase of habitat connectivity combined with targeted management of exotic species.
Edwardsiella piscicida infection reshapes the intestinal microbiome and metabolome of big-belly seahorses: mechanistic insights of synergistic actions of virulence factors
Authors: Zhang Lele , Wang Fang , Jia Longwu , Yan Hansheng , Gao Longkun , Tian Yanan , Su Xiaolei , Zhang Xu , Lv Chunhui , Ma Zhenhao , Xue Yuanyuan , Lin Qiang , Wang Kai
Published: May 2023

Uncovering the mechanism underlying the pathogenesis of Edwardsiella piscicida-induced enteritis is essential for global aquaculture. In the present study, we identified E. piscicida as a lethal pathogen of the big-belly seahorse (Hippocampus abdominalis) and revealed its pathogenic pattern and characteristics by updating our established bacterial enteritis model and evaluation system. Conjoint analysis of metagenomic and metabolomic data showed that 15 core virulence factors could mutually coordinate the remodeling of intestinal microorganisms and host metabolism and induce enteritis in the big-belly seahorse. Specifically, the Flagella, Type IV pili, and Lap could significantly increase the activities of the representative functional pathways of both flagella assembly and bacterial chemotaxis in the intestinal microbiota (P < 0.01) to promote pathogen motility, adherence, and invasion. Legiobactin, IraAB, and Hpt could increase ABC transporter activity (P < 0.01) to compete for host nutrition and promote self-replication. Capsule1, HP-NAP, and FarAB could help the pathogen to avoid phagocytosis. Upon entering epithelial cells and phagocytes, Bsa T3SS and Dot/Icm could significantly increase bacterial secretion system activity (P < 0.01) to promote the intracellular survival and replication of the pathogen and the subsequent invasion of the neighboring tissues. Finally, LPS3 could significantly increase lipopolysaccharide biosynthesis (P < 0.01) to release toxins and kill the host. Throughout the pathogenic process, BopD, PhoP, and BfmRS significantly activated the two-component system (P < 0.01) to coordinate with other VFs to promote deep invasion. In addition, the levels of seven key metabolic biomarkers, Taurine, L-Proline, Uridine, L-Glutamate, Glutathione, Xanthosine, and L-Malic acid, significantly decreased (P < 0.01), and they can be used for characterizing E. piscicida infection. Overall, the present study systematically revealed how a combination of virulence factors mediate E. piscicida-induced enteritis in fish for the first time, providing a theoretical reference for preventing and controlling this disease in the aquaculture of seahorses and other fishes.
Potential causal role of synovial complement system activation in the development of post-traumatic osteoarthritis after anterior cruciate ligament injury or meniscus tear
Authors: Holers V. Michael , Frank Rachel M. , Clauw Andrew , Seifert Jennifer , Zuscik Michael , Asokan Sakthi , Striebich Christopher , Clay Michael R. , Moreland Larry W. , Banda Nirmal K.
Published: May 2023

Anterior cruciate ligament (ACL) injury and meniscal tear (MT) are major causal factors for developing post-traumatic osteoarthritis (PTOA), but the biological mechanism(s) are uncertain. After these structural damages, the synovium could be affected by complement activation that normally occurs in response to tissue injury. We explored the presence of complement proteins, activation products, and immune cells, in discarded surgical synovial tissue (DSST) collected during arthroscopic ACL reconstructive surgery, MT-related meniscectomy and from patients with OA. Multiplexed immunohistochemistry (MIHC) was used to determine the presence of complement proteins, receptors and immune cells from ACL, MT, OA synovial tissue vs. uninjured controls. Examination of synovium from uninjured control tissues did not reveal the presence of complement or immune cells. However, DSST from patients undergoing ACL and MT repair demonstrated increases in both features. In ACL DSST, a significantly higher percentage of C4d+, CFH+, CFHR4+ and C5b-9+ synovial cells were present compared with MT DSST, but no major differences were seen between ACL and OA DSST. Increased cells expressing C3aR1 and C5aR1, and a significant increase in mast cells and macrophages, were found in ACL as compared to MT synovium. Conversely, the percentage of monocytes was increased in the MT synovium. Our data demonstrate that complement is activated in the synovium and is associated with immune cell infiltration, with a more pronounced effect following ACL as compared to MT injury. Complement activation, associated with an increase in mast cells and macrophages after ACL injury and/or MT, may contribute to the development of PTOA.
Relationship between histone demethylase LSD family and development and prognosis of gastric cancer
Authors: Dong Liyan , Zhu Jiaxing , Deng Anyi , Wei Junping , Li Jiawei , Mao Xinru , Jia Zhenghu
Published: May 2023

Objective

to elucidate the correlation between histone demethylase and gastric cancer

Research object

histone demethylase and gastric cancer

Results

As one of the important regulatory mechanisms in molecular biology and epigenetics, histone modification plays an important role in gastric cancer including downstream gene expression regulation and epigenetics effect. Both histone methyltransferase and histone demethylases are involved in the formation and maintaining different of histone methylation status, which in turn through a variety of vital molecules and signaling pathways involved in the recognition of histone methylation modification caused by the downstream biological process, eventually participate in the regulation of chromatin function, and with a variety of important physiological activities, especially closely related to the occurrence of gastric cancer and embryonic development.

Conclusion

This paper intends to review the research progress in this field from the aspects of histone methylation modification and the protein structure, catalytic mechanism and biological function of the important histone demethylases LSD1 and LSD2, in order to provide the theoretical reference for further understanding and exploration of histone demethylases in development and prognosis of gastric cancer.
Risk factors and characteristics influencing humoral response to COVID-19 vaccination in patients after allogeneic stem cell transplantation
Authors: Hütter-Krönke Marie Luise , Neagoie Adela , Blau Igor Wolfgang , Wais Verena , Vuong Lam , Gantner Andrea , Ahn Johann , Penack Olaf , Schnell Jacqueline , Nogai Klaus Axel , Eberspächer Bettina , Saadati Maral , Benner Axel , Bullinger Lars , Döhner Hartmut , Bunjes Donald , Sala Elisa
Published: May 2023

Introduction

Vaccination against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is approved and recommended for immunocompromised patients such as patients after allogeneic stem cell transplantation (allo-SCT). Since infections represent a relevant cause of transplant related mortality we analyzed the advent of immunization to SARS-CoV-2 vaccination in a bicentric population of allogeneic transplanted patients.

Methods

We retrospectively analyzed data of allo-SCT recipients in two German transplantation centers for safety and serologic response after two and three SARS-CoV-2 vaccinations. Patients received mRNA vaccines or vector-based vaccines. All patients were monitored for antibodies against SARS-CoV2-spike protein (anti-S-IgG) with an IgG ELISA assay or an EIA Assay after two and three doses of vaccination.

Results

A total of 243 allo-SCT patients underwent SARS-CoV-2 vaccination. The median age was 59 years (range 22-81). While 85% of patients received two doses of mRNA vaccines, 10% had vector-based vaccines and 5% received a mixed vaccination. The two vaccine doses were well tolerated with only 3% patients developing a reactivation of graft versus host disease (GvHD). Overall, 72% of patients showed a humoral response after two vaccinations. In the multivariate analysis age at time of allo-SCT (p=0.0065), ongoing immunosuppressive therapy (p= 0.029) and lack of immune reconstitution (CD4-T-cell counts <200/μl, p< 0.001) were associated with no response. Sex, intensity of conditioning and the use of ATG showed no influence on seroconversion. Finally, 44 out of 69 patients that did not respond after the second dose received a booster and 57% (25/44) showed a seroconversion.

Discussion

We showed in our bicentric allo-SCT patient cohort, that a humoral response could be achieve after the regular approved schedule, especially for those patients who underwent immune reconstitution and were free from immunosuppressive drugs. In over 50% of the initial non-responders after 2-dose vaccination, a seroconversion can be achieved by boostering with a third dose.
Reduced immunogenicity of a live Salmonella enterica serovar Typhimurium vaccine in aged mice
Authors: Allen Jessica C. , Toapanta Franklin R. , Baliban Scott M. , Sztein Marcelo B. , Tennant Sharon M.
Published: May 2023

Introduction

Non-typhoidal Salmonella (NTS) is responsible for a high burden of foodborne infections and deaths worldwide. In the United States, NTS infections are the leading cause of hospitalizations and deaths due to foodborne illnesses, and older adults (≥65 years) are disproportionately affected by Salmonella infections. Due to this public health concern, we have developed a live attenuated vaccine, CVD 1926 (I77 ΔguaBA ΔclpP ΔpipA ΔhtrA), against Salmonella enterica serovar Typhimurium, a common serovar of NTS. Little is known about the effect of age on oral vaccine responses, and due to the decline in immune function with age, it is critical to evaluate vaccine candidates in older age groups during early product development.

Methods

In this study, adult (six-to-eight-week-old) and aged (18-month-old) C57BL/6 mice received two doses of CVD 1926 (109 CFU/dose) or PBS perorally, and animals were evaluated for antibody and cell-mediated immune responses. A separate set of mice were immunized and then pre-treated with streptomycin and challenged orally with 108 CFU of wild-type S. Typhimurium SL1344 at 4 weeks postimmunization.

Results

Compared to PBS-immunized mice, adult mice immunized with CVD 1926 had significantly lower S. Typhimurium counts in the spleen, liver, and small intestine upon challenge. In contrast, there were no differences in bacterial loads in the tissues of vaccinated versus PBS aged mice. Aged mice exhibited reduced Salmonella-specific antibody titers in the serum and feces following immunization with CVD 1926 compared to adult mice. In terms of T cell responses (T-CMI), immunized adult mice showed an increase in the frequency of IFN-γ- and IL-2-producing splenic CD4 T cells, IFN-γ- and TNF-α-producing Peyer’s Patch (PP)-derived CD4 T cells, and IFN-γ- and TNF-α-producing splenic CD8 T cells compared to adult mice administered PBS. In contrast, in aged mice, T-CMI responses were similar in vaccinated versus PBS mice. CVD 1926 elicited significantly more PP-derived multifunctional T cells in adult compared to aged mice.

Conclusion

These data suggest that our candidate live attenuated S. Typhimurium vaccine, CVD 1926, may not be sufficiently protective or immunogenic in older humans and that mucosal responses to live-attenuated vaccines decrease with increasing age.
Preparation of terminal blend/ grafting activated crumb rubber composite modified asphalt based on response surface methodology
Authors: Xie Juan , Zhao Xucheng , Zhang Yongning , Yu Fan , Luo Haochen , Chen Xueru , He Wen
Published: May 2023

Recycling waste tires, crushing them into crumb rubber (CR) and adding them to asphalt can effectively improve the performance and prolong the service life of asphalt pavement. However, the crumb rubber modified asphalt (CRMA) prepared by aforementioned process is prone to segregation during storage and transportation. The terminal blend rubber asphalt (TB) prepared with fine rubber powder by high-speed shearing at high temperature for long time, which effectively improves the storage stability and working performance of crumb rubber modified asphalt, but reduces the high-temperature performance. In this study, grafting activated crumb rubber (GACR) was incorporated into TB to improve its high temperature performance without impairing storage stability. Using shearing temperature, shearing time and grafting activated crumb rubber content as influencing factors, the response surface method (RSM) was carried out to optimize the preparation process. The results indicated that 180°C was a critical temperature, and the swelling of crumb rubber dominated with the temperature below it, but the desulfurization prevailed with the temperature above it. The extension of time favored the swelling of crumb rubber at low temperature but promoted desulfurization at high temperature. With the increase of crumb rubber content, the high temperature performance of modified asphalt improved whereas the storage stability deteriorated. According to the determination of response values and the prediction of optimal values, the suitable preparation conditions and parameters were recommended as shearing temperature of 190°C, shearing time of 90 min, and GACR content of 15%. The composite modified asphalt prepared through the optimized process showed good high temperature stability and storage stability.
Pronounced Enhancement in Radiosensitization of Esophagus Cancer Cultivated in Docosahexaenoic Acid via the PPAR -γ Activation
Authors: Yang Ying , Xu Ying , Zhao Congzhao , Zhang Lirong , Nuerbol Aslibek , Wang Lili , Jiao Yang
Published: May 2023

Docosahexaenoic acid (DHA) has been reported to suppress the tumor growth and improve prognosis and has been used to cooperate with many other chemotherapy medicines. Up to now, surveys focused on the Interaction between DHA and radiation are relatively modest. Our study sought to evaluate the radiosensitivity changes caused by DHA on esophageal cancer cells. We selected TE-1 and TE-10 esophagus cancer cells as models and performed routine cell proliferation assay and cloning assay to detect the impact of DHA combined with X-ray. We used cell cycle assay, lipid peroxidation assay, comet assay, and apoptosis assay to unearth the potential causes. We also launched a mouse transplanted tumor experiment to verify the synergetic effect of DHA and irradiation. Finally, a western blot assay was used to find a novel mechanism. As a result, DHA improved TE-1 and TE-10 radiosensitivity in vivo and in vitro. What's more, PPAR-γ expression increased due to the DHA supplement. Inhibiting PPAR-γ could attenuate benefits brought out by DHA somehow. Due to its explicit usage and convenience, DHA would serve as an adjuvant therapy before radiotherapy if the clinical trials indicated positive.
Influence of olive cake dietary supplementation on fecal microbiota of dairy cows
Authors: Russo Nunziatina , Floridia Viviana , D’Alessandro Enrico , Lopreiato Vincenzo , Pino Alessandra , Chiofalo Vincenzo , Caggia Cinzia , Liotta Luigi , Randazzo Cinzia Lucia
Published: May 2023

Olive by-products represent a valuable low-price feed supplement for animal nutrition. In the present study, the effect of the dietary destoned olive cake supplementation, on both composition and dynamics of the fecal bacterial biota of cow, was assessed by Illumina MiSeq analysis of the 16S rRNA gene. In addition, metabolic pathways were predicted by using the PICRUSt2 bioinformatic tool. Eighteen lactating cows, according to the body condition score, the days from calving, and the daily milk production were homogeneously allocated into two groups, control or experimental, and subjected to different dietary treatments. In detail, the experimental diet contained, along with the components of the control one, 8% of destoned olive cake. Metagenomics data revealed significant differences in abundance rather than in richness between the two groups. Results showed that Bacteroidota and Firmicutes were identified as the dominant phyla, accounting for over 90% of the total bacterial population. The Desulfobacterota phylum, able to reduce sulfur compounds, was detected only in fecal samples of cows allocated to the experimental diet whereas the Elusimicrobia phylum, a common endosymbiont or ectosymbiont of various flagellated protists, was detected only in cows subjected to the control diet. In addition, both Oscillospiraceae and Ruminococcaceae families were mainly found in the experimental group whereas fecal samples of control cows showed the presence of Rikenellaceae and Bacteroidaceae families, usually associated with the high roughage or low concentrate diet. Based on the PICRUSt2 bioinformatic tool, pathways related to carbohydrate, fatty acid, lipid, and amino acids biosynthesis were mainly up regulated in the experimental group. On the contrary, in the control group, the metabolic pathways detected with the highest occurrence were associated with amino acids biosynthesis and degradation, aromatic compounds degradation, nucleosides and nucleotides biosynthesis. Hence, the present study confirms that the destoned olive cake is a valuable feed supplement able to modulate the fecal microbiota of cows. Further studies will be conducted in order to deepen the inter-relationships between the GIT microbiota and the host.
Anthocyanins from Malus spp. inhibit the activity of Gymnosporangium yamadae by downregulating the expression of WSC, RLM1, and PMA1
Authors: Wang Yu , An Hong , Guo Yan-Nan , Wang Qian , Shang Yuan-Yuan , Chen Ming-Kun , Liu Yi-Xin , Meng Jia-Xin , Zhang Shuang-Yu , Wei Jun , Li Hou-Hua
Published: May 2023

Malus plants are frequently devastated by the apple rust caused by Gymnosporangium yamadae Miyabe. When rust occurs, most Malus spp. and cultivars produce yellow spots, which are more severe, whereas a few cultivars accumulate anthocyanins around rust spots, forming red spots that inhibit the expansion of the affected area and might confer rust resistance. Inoculation experiments showed that Malus spp. with red spots had a significantly lower rust severity. Compared with M. micromalus, M. ‘Profusion’, with red spots, accumulated more anthocyanins. Anthocyanins exhibited concentration-dependent antifungal activity against G. yamadae by inhibiting teliospores germination. Morphological observations and the leakage of teliospores intracellular contents evidenced that anthocyanins destroyed cell integrity. Transcriptome data of anthocyanins-treated teliospores showed that differentially expressed genes were enriched in cell wall and membrane metabolism-related pathways. Obvious cell atrophy in periodical cells and aeciospores was observed at the rust spots of M. ‘Profusion’. Moreover, WSC, RLM1, and PMA1 in the cell wall and membrane metabolic pathways were progressively downregulated with increasing anthocyanins content, both in the in vitro treatment and in Malus spp. Our results suggest that anthocyanins play an anti-rust role by downregulating the expression of WSC, RLM1, and PMA1 to destroy the cell integrity of G. yamadae.
Dextran sulfate from Leuconostoc mesenteroides B512F exerts potent antiviral activity against SARS-CoV-2 in vitro and in vivo
Authors: Andreu Sabina , von Kobbe Cayetano , Delgado Pilar , Ripa Inés , Buzón María José , Genescà Meritxell , Gironès Núria , del Moral-Salmoral Javier , Ramírez Gustavo A. , Zúñiga Sonia , Enjuanes Luis , López-Guerrero José Antonio , Bello-Morales Raquel
Published: May 2023

The emergent human coronavirus SARS-CoV-2 and its resistance to current drugs makes the need for new potent treatments for COVID-19 patients strongly necessary. Dextran sulfate (DS) polysaccharides have long demonstrated antiviral activity against different enveloped viruses in vitro. However, their poor bioavailability has led to their abandonment as antiviral candidates. Here, we report for the first time the broad-spectrum antiviral activity of a DS-based extrapolymeric substance produced by the lactic acid bacterium Leuconostoc mesenteroides B512F. Time of addition assays with SARS-CoV-2 pseudoviruses in in vitro models confirm the inhibitory activity of DSs in the early stages of viral infection (viral entry). In addition, this exopolysaccharide substance also reports broad-spectrum antiviral activity against several enveloped viruses such as SARS-CoV-2, HCoV229E, HSV-1, in in vitro models and in human lung tissue. The toxicity and antiviral capacity of DS from L. mesenteroides was tested in vivo in mouse models which are susceptible to SARS-CoV-2 infection. The described DS, administered by inhalation, a new route of administration for these types of polymers, shows strong inhibition of SARS-CoV-2 infection in vivo, significantly reducing animal mortality and morbidity at non-toxic doses. Therefore, we suggest that it may be considered as a potential candidate for antiviral therapy against SARS-CoV-2.
Anesthesia and analgesia for experimental craniotomy in mice and rats: a systematic scoping review comparing the years 2009 and 2019
Authors: King Hannah , Reiber Maria , Philippi Vanessa , Stirling Helen , Aulehner Katharina , Bankstahl Marion , Bleich André , Buchecker Verena , Glasenapp Aylina , Jirkof Paulin , Miljanovic Nina , Schönhoff Katharina , von Schumann Lara , Leenaars Cathalijn , Potschka Heidrun
Published: May 2023

Experimental craniotomies are a common surgical procedure in neuroscience. Because inadequate analgesia appears to be a problem in animal-based research, we conducted this review and collected information on management of craniotomy-associated pain in laboratory mice and rats. A comprehensive search and screening resulted in the identification of 2235 studies, published in 2009 and 2019, describing craniotomy in mice and/or rats. While key features were extracted from all studies, detailed information was extracted from a random subset of 100 studies/year. Reporting of perioperative analgesia increased from 2009 to 2019. However, the majority of studies from both years did not report pharmacologic pain management. Moreover, reporting of multimodal treatments remained at a low level, and monotherapeutic approaches were more common. Among drug groups, reporting of pre- and postoperative administration of non-steroidal anti-inflammatory drugs, opioids, and local anesthetics in 2019 exceeded that of 2009. In summary, these results suggest that inadequate analgesia and oligoanalgesia are persistent issues associated with experimental intracranial surgery. This underscores the need for intensified training of those working with laboratory rodents subjected to craniotomies.

Systematic review registration

https://osf.io/7d4qe.
Gene therapy: an emerging therapy for hair cells regeneration in the cochlea
Authors: Wang Jipeng , Zheng Jianwei , Wang Haiyan , He Haoying , Li Shuang , Zhang Ya , Wang You , Xu Xiaoxiang , Wang Shuyi
Published: May 2023

Sensorineural hearing loss is typically caused by damage to the cochlear hair cells (HCs) due to external stimuli or because of one’s genetic factors and the inability to convert sound mechanical energy into nerve impulses. Adult mammalian cochlear HCs cannot regenerate spontaneously; therefore, this type of deafness is usually considered irreversible. Studies on the developmental mechanisms of HC differentiation have revealed that nonsensory cells in the cochlea acquire the ability to differentiate into HCs after the overexpression of specific genes, such as Atoh1, which makes HC regeneration possible. Gene therapy, through in vitro selection and editing of target genes, transforms exogenous gene fragments into target cells and alters the expression of genes in target cells to activate the corresponding differentiation developmental program in target cells. This review summarizes the genes that have been associated with the growth and development of cochlear HCs in recent years and provides an overview of gene therapy approaches in the field of HC regeneration. It concludes with a discussion of the limitations of the current therapeutic approaches to facilitate the early implementation of this therapy in a clinical setting.
Impact of hospital characteristics on implementation of a Pediatric Early Warning System in resource-limited cancer hospitals
Authors: Abutineh Farris , Graetz Dylan E. , Muniz-Talavera Hilmarie , Ferrara Gia , Puerto-Torres Maria , Chen Yichen , Gillipelli Srinithya R. , Elish Paul , Gonzalez-Ruiz Alejandra , Alfonso Carreras Yvania , Alvarez Shillel , Arce Cabrera Daniela , Arguello Vargas Deiby , Armenta Cruz Miriam , Barra Camila , Calderon Sotelo Patricia , Carpio Zulma , Chavez Rios Mayra , Covarrubias Daniela , de Leon Vasquez Lucy , Diaz Coronado Rosdali , Fing Soto Ever Amilcar , Gomez-Garcia Wendy , Hernandez Cinthia , Juarez Tobias María Susana , Leon Esmeralda , Loeza Oliva Jose de Jesus , Mendez Alejandra , Miller Kenia , Montalvo Cozar Erika , Negroe Ocampo Natalia del Carmen , Penafiel Eulalia , Pineda Estuardo , Rios Ligia , Rodriguez Ordonez Esperanza , Soto Chavez Veronica , Devidas Meenakshi , Agulnik Asya
Published: May 2023

Background

Pediatric Early Warning Systems (PEWS) aid in identification of deterioration in hospitalized children with cancer but are underutilized in resource-limited settings. Proyecto EVAT is a multicenter quality improvement (QI) collaborative in Latin America to implement PEWS. This study investigates the relationship between hospital characteristics and time required for PEWS implementation.

Methods

This convergent mixed-methods study included 23 Proyecto EVAT childhood cancer centers; 5 hospitals representing quick and slow implementers were selected for qualitative analysis. Semi-structured interviews were conducted with 71 stakeholders involved in PEWS implementation. Interviews were recorded, transcribed and translated to English, then coded using a priori and novel codes. Thematic content analysis explored the impact of hospital characteristics and QI experience on time required for PEWS implementation and was supplemented by quantitative analysis exploring the relationship between hospital characteristics and implementation time.

Results

In both quantitative and qualitative analysis, material and human resources to support PEWS significantly impacted time to implementation. Lack of resources produced various obstacles that extended time necessary for centers to achieve successful implementation. Hospital characteristics, such as funding structure and type, influenced PEWS implementation time by determining their resource-availability. Prior hospital or implementation leader experience with QI, however, helped facilitate implementation by assisting implementers predict and overcome resource-related challenges.

Conclusions

Hospital characteristics impact time required to implement PEWS in resource-limited childhood cancer centers; however, prior QI experience helps anticipate and adapt to resource challenges and more quickly implement PEWS. QI training should be a component of strategies to scale-up use of evidence-based interventions like PEWS in resource-limited settings.
Overall survival and cancer-specific survival were improved in local treatment of metastatic prostate cancer
Authors: Miao Qi , Wei Zhihao , Liu Chenchen , Ye Yuzhong , Cheng Gong , Song Zhengshuai , Chen Kailei , Zhang Yunxuan , Chen Jiawei , Yue Changjie , Ruan Hailong , Zhang Xiaoping
Published: May 2023

Background

For metastatic prostate cancer (mPCa), radical prostatectomy (RP) and radiation therapy (RT) may improve overall survival (OS) and cancer-specific survival (CSS). Compared with RT, RP shows significant advantages in improving patient outcomes. External beam radiation therapy (EBRT) even slightly elevates CSM with no statistical difference in OS compared with no local treatment (NLT).

Objective

To evaluate OS and CSS after local treatment (LT) (including RP and RT) versus NLT in mPCa.

Design, setting, and participants

Within the Surveillance, Epidemiology and End Results (SEER) database (2000-2018), 20098 patients with metastatic prostate cancer were selected in this study, of which 19433 patients had no local treatment, 377 patients with radical prostate treatment, and 288 patients with RT.

Outcome measurements and statistical analysis

Multivariable competing risks regression analysis after propensity score matching (PSM) was used to calculate CSM. Multivariable Cox regression analysis was used to identify the risk factors. Kaplan-Meier methods were used to calculate OS.

Results and limitations

A total of 20098 patients were included: NLT (n = 19433), RP (n=377) and RT (n=288). In a competing risk regression analysis after PSM (ratio 1:1), RP resulted in a significantly lower CSM (hazard ratio [HR] 0.36, 95% confidence interval [CI] 0.29-0.45) than NLT, while RT showed a slightly lower CSM (HR 0.77, 95% CI 0.63-0.95). In a competing risk regression analysis after PSM (ratio 1:1), RP led to a lower CSM (HR 0.56, 95% CI 0.41-0.76) versus RT. As for all-cause mortality (ACM), RP (HR 0.37, 95% CI 0.31-0.45) and RT (HR 0.66, 95% CI 0.56-0.79). also showed a downward trend. In terms of OS, RP and RT significantly improved the survival probability compared with NLT, with the effect of RP being more pronounced. Obviously, older age, Gleason scores ≥8, AJCC T3-T4 stage, AJCC N1, AJCC M1b-M1c were all associated with higher CSM (P <0.05). The same results held true for ACM. The limitation of this article is that it is not possible to assess the effect of differences in systemic therapy on CSM in mPCa patients and clinical trials are needed to verify the results.

Conclusions

For patients with mPCa, both RP and RT are beneficial to patients, and the efficacy of RP is better than RT from the perspective of CSM and ACM. Older age, higher gleason scores and the more advanced AJCC TNM stage all put patients at higher risk of dying.

Patient summary

A large population-based cancer database showed that in addition to first-line therapy (hormonal treatment), RP and radiotherapy can also benefit patients with mPCa.
Mendelian randomization to explore the direct or mediating associations between socioeconomic status and lung cancer
Authors: Wu Hong , Yang Jing , Wang Hui , Li Lei
Published: May 2023

Objective

The purpose of this study was to verify whether there are direct or mediated causal associations between socioeconomic status and lung cancer.

Methods

Pooled statistics were obtained from corresponding genome-wide association studies. The inverse-variance weighted, weighted median, MR−Egger, MR-PRESSO and contamination-mixture methods were used as supplements to Mendelian randomization (MR) statistical analysis. Cochrane’s Q value and the MR−Egger intercept were used for sensitivity analysis.

Results

In the univariate MR analysis, household income and education had protective effects on overall lung cancer (income: P = 5.46×10-4; education: P = 4.79×10-7) and squamous cell lung cancer (income: P = 2.67×10-3; education: P = 1.42×10-10). Smoking and BMI had adverse effects on overall lung cancer (smoking: P = 2.10×10-7; BMI: P = 5.67×10-4) and squamous cell lung cancer (smoking: P = 5.02×10-6; BMI: P = 2.03×10-7). Multivariate MR analysis found that smoking and education were independent risk factors for overall lung cancer (smoking: P = 1.96×10-7; education: P = 3.11×10-3), while smoking was an independent risk factor for squamous cell lung cancer (P = 2.35×10-6). Smoking, education, and household income mediate the effect of BMI on overall lung cancer (smoking 50.0%, education 49.2%, income 25.3%) and squamous cell lung cancer (smoking 34.8%, education 30.8%, income 21.2%). Smoking, education, and BMI mediate the effect of income on overall lung cancer (smoking 13.9%, education 54.8%, BMI 9.4%) and squamous cell lung cancer (smoking 12.6%, education 63.3%, BMI 11.6%). Smoking, BMI, and income mediate the effect of education on squamous cell lung cancer (smoking 24.0%, BMI 6.2%, income 19.4%).

Conclusion

Income, education, BMI, and smoking are causally associated with both overall lung cancer and squamous cell lung cancer. Smoking and education are independent association factors for overall lung cancer, while smoking is an independent association factor for squamous cell lung cancer. Smoking and education also play important mediating roles in overall lung cancer and squamous cell lung cancer. No causal relationship was found between multiple risk factors associated with socioeconomic status and lung adenocarcinoma.
Successful treatment of metastatic uveal melanoma with ipilimumab and nivolumab after severe progression under tebentafusp: a case report
Authors: Reiter Selina , Schroeder Christopher , Broche Julian , Sinnberg Tobias , Bonzheim Irina , Süsskind Daniela , Flatz Lukas , Forschner Andrea
Published: May 2023

Metastatic uveal melanoma (UM) is a rare form of melanoma differing from cutaneous melanoma by etiology, prognosis, driver mutations, pattern of metastases and poor response rate to immune checkpoint inhibitors (ICI). Recently, a bispecific gp100 peptide-HLA-directed CD3 T cell engager, tebentafusp, has been approved for the treatment of HLA-A*02:01 metastatic or unresectable UM. While the treatment regime is complex with weekly administrations and close monitoring, the response rate is limited. Only a few data exist on combined ICI in UM after previous progression on tebentafusp. In this case report, we present a patient with metastatic UM who first suffered extensive progression under treatment with tebentafusp but in the following had an excellent response to combined ICI. We discuss possible interactions that could explain responsiveness to ICI after pretreatment with tebentafusp in advanced UM.
Correction of narrow nostril deformity secondary to cleft lip: indications for different surgical methods and a retrospective study
Authors: Wei Hongpu , Xu Xiaofeng , Wan Teng , Yang Yusheng , Zhang Yong , Wu Yilai , Liang Yun
Published: May 2023

Background

Cleft lip and/or palate (CLP) can lead to severe nasolabial deformities that significantly affect the appearance of the patient. Among all types of nasolabial deformities, narrow nostril deformities are the most troublesome, causing poor and unstable surgical outcomes. The purpose of this study was to develop an algorithm for surgical method selection for revision of narrow nostril deformities secondary to CLP based on retrospective clinical data.

Materials and methods

Patients with narrow nostril deformities secondary to CLP were enrolled in the study. Before surgery, patients' clinical data were collected and the width of the nasal floor and the length of the alar rim were measured. Surgical methods were determined according to the measurements. After surgery, a nostril retainer was applied for 6 months to consolidate and maintain the nostril shape. The surgical method and postsurgical changes were recorded for the final summary of the algorithm to select surgical methods for narrow nostril deformities.

Results

The data from 9 patients were analyzed. According to the width of the nasal floor and the length of the alar rim, correct surgical methods were determined. Four patients received nasolabial skin flaps to widen the soft tissue of the nasal floor. Three patients received upper lip scar tissue flaps to treat the narrow nasal floor. For the short alar rim, free alar composite tissue flap or narrowing of the nostril of the noncleft side was recommended.

Conclusion

The width of the nasal floor and the length of the alar rim are critical elements to consider when selecting the correct surgical method for revising narrow nostril deformities secondary to CLP. The proposed algorithm provides a reference for selecting surgical methods in future clinical practice.
Design and optimization of a compact quasi-isochronous 180-deg transport arc with suppressed CSR-induced emittance growth
Authors: Zhang Chengyi , Jiao Yi
Published: May 2023

Preserving the beam quality of a high-brightness electron beam is a noteworthy issue when delivering the electron bunch through a beam transfer line. In a beam transfer line with a large deflection angle, e.g., a 180-deg transport arc comprised of a large amount of dipoles, emission of coherent synchrotron radiation (CSR) can lead to transverse emittance dilution. In addition, the longitudinal dispersion may cause undesirable bunch length variation. Both effects can degrade beam quality. Nevertheless, design and optimization of a 180-deg transport arc that can be well applied to practical applications is a challenging problem, considering the practical nonlinear effects of a real lattice and the contributions of transient CSR at the dipole edges and CSR in the subsequent drifts. In this study, we present the design and optimization of a compact 180-deg transport arc comprised of multi-triple-bend achromat (TBA) cells, aiming at suppressing the CSR-induced emittance growth and avoiding bunch length variation simultaneously. The TBA cells and optics along the arc are adjusted to suppress the CSR-induced emittance growth and bunch length variation cell by cell, after which a multi-objective optimization of the arc is conducted. Practical considerations including lattice nonlinear effects and a full one-dimensional CSR model (including transient CSR and CSR in drifts) are taken into account.