bluuebunny/crossref_metadata_2025_split huggingface dataset:
Programmed death ligand 1 gene silencing in murine glioma models reveals cell line-specific modulation of tumor growth in vivo
Authors: Blomberg Evelina , Silginer Manuela , Roth Patrick , Weller Michael 
Published: September 2022

Abstract

Background
Glioblastoma is the most common brain tumor in adults and virtually incurable. Therefore, new therapeutic strategies are urgently needed. Immune checkpoint inhibition has not shown activity in various phase III trials and intra- as well as intertumoral expression of programmed death ligand 1 (PD-L1) varies in glioblastoma.

Methods
We abrogated constitutive PD-L1 gene expression by CRISPR/Cas9 in murine glioma models and characterized the consequences of gene deletion in vitro and in vivo.

Results
A heterogeneous expression of Pdl1 mRNA and PD-L1 protein was detected in the glioma cell panel in vitro and in vivo. PD-L1, but not PD-L2, was inducible by interferon β and γ. Co-culture with splenocytes induced PD-L1 expression in GL-261 and SMA-560, but not in CT-2A cells, in an interferon γ-dependent manner. Conversely, Pdl1 gene silencing conferred a survival benefit in CT-2A, but not in the other 2 models. Accordingly, PD-L1 antibody prolonged survival in CT-2A glioma-bearing mice. This activity required PD-L1 expression on tumor rather than host cells, and the survival gain mediated by PD-L1 loss was reproduced in immune-deficient RAG−/− mice.

Conclusions
PD-L1 is expressed and interferon-inducible in murine glioma cell lines. PD-L1 has model-specific roles for tumor growth. Future studies need to determine which subset of glioblastoma patients may benefit from PD-L1 antagonism as part of a multimodality therapeutic approach to glioblastoma.
Effects of nutrition on metabolic and endocrine outcomes in women with polycystic ovary syndrome: an umbrella review of meta-analyses of randomized controlled trials
Authors: Moslehi Nazanin , Zeraattalab-Motlagh Sheida , Rahimi Sakak Fatemeh , Shab-Bidar Sakineh , Tehrani Fahimeh Ramezani , Mirmiran Parvin 
Published: September 2022

AbstractContextNumerous meta-analyses have been conducted on the effects of nutritional interventions on various health outcomes in women with polycystic ovary syndrome (PCOS). However, the strength of the evidence and its clinical significance are unclear.ObjectiveThis umbrella review aimed to summarize the effects of nutritional interventions on women with PCOS and assess the strength of the evidence.Data SourcesPubMed, Scopus, and Web of Science were searched from inception until March 17, 2021.Data ExtractionMeta-analyses of randomized clinical trials (RCTs) that examined the impact of dietary modifications or supplementations on women with PCOS were selected. Data extraction, quality assessments of the meta-analyses, and evaluation of the strength of the evidence were conducted independently by 2 investigators and confirmed by a third.Data AnalysisTwenty-eight RCT meta-analyses were included, reporting 40 different outcomes. Lower carbohydrate, Dietary Approaches to Stop Hypertension, or lower glycemic index/load diets in women with PCOS significantly improved some anthropometric and metabolic characteristics (with very low to low certainty). Probiotics/synbiotics reduced fasting plasma glucose, fasting insulin (FI), and homeostasis model assessment–estimated insulin resistance (HOMA-IR) (with moderate to high certainty). Curcumin supplementation decreased fasting plasma glucose, FI, and HOMA-IR (with moderate certainty). Fish oil supplementation decreased FI and HOMA-IR, and omega-3 reduced triglycerides (with moderate certainty). There were also improvements in FI after taking vitamin D or inositol supplements (with moderate certainty). Supplementation with fish oil increased adiponectin (with high certainty), and probiotics/synbiotics reduced total testosterone (with moderate certainty). In subfertile women with PCOS, inositol increased the ovulation rates (with moderate certainty).ConclusionThere was no high-certainty evidence that diets alone in women with PCOS improved health or reproductive outcomes. Supplementation with vitamin D, probiotics/synbiotics, omega-3, inositol, and curcumin showed favorable effects on some metabolic outcomes. Probiotics/synbiotics possibly reduces total testosterone, and inositol stimulates ovulation in women with PCOS.RegistrationPROSPERO registration no. CRD42021251496.
Structural basis for proenzyme maturation, substrate recognition, and ligation by a hyperactive peptide asparaginyl ligase
Authors: Hu Side , El Sahili Abbas , Kishore Srujana , Wong Yee Hwa , Hemu Xinya , Goh Boon Chong , Zhipei Sang , Wang Zhen , Tam James P , Liu Chuan-Fa , Lescar Julien 
Published: September 2022

AbstractPeptide ligases are versatile enzymes that can be utilized for precise protein conjugation for bioengineering applications. Hyperactive peptide asparaginyl ligases (PALs), such as butelase-1, belong to a small class of enzymes from cyclotide-producing plants that can perform site-specific, rapid ligation reactions after a target peptide asparagine/aspartic acid (Asx) residue binds to the active site of the ligase. How PALs specifically recognize their polypeptide substrates has remained elusive, especially at the prime binding side of the enzyme. Here we report crystal structures that capture VyPAL2, a catalytically efficient PAL from Viola yedoensis, in an activated state, with and without a bound substrate. The bound structure shows one ligase with the N-terminal polypeptide tail from another ligase molecule trapped at its active site, revealing how Asx inserts in the enzyme’s S1 pocket and why a hydrophobic residue is required at the P2′ position. Besides illustrating the anchoring role played by P1 and P2′ residues, these results uncover a role for the Gatekeeper residue at the surface of the S2 pocket in shifting the nonprime portion of the substrate and, as a result, the activity toward ligation or hydrolysis. These results suggest a picture for proenzyme maturation in the vacuole and will inform the rational design of peptide ligases with tailored specificities.
Stomatal conductance tracks soil-to-leaf hydraulic conductance in faba bean and maize during soil drying
Authors: Müllers Yannik , Postma Johannes A , Poorter Hendrik , van Dusschoten Dagmar 
Published: September 2022

Abstract
Although regulation of stomatal conductance is widely assumed to be the most important plant response to soil drying, the picture is incomplete when hydraulic conductance from soil to the leaf, upstream of the stomata, is not considered. Here, we investigated to what extent soil drying reduces the conductance between soil and leaf, whether this reduction differs between species, how it affects stomatal regulation, and where in the hydraulic pathway it occurs. To this end, we noninvasively and continuously measured the total root water uptake rate, soil water potential, leaf water potential, and stomatal conductance of 4-week-old, pot-grown maize (Zea mays) and faba bean (Vicia faba) plants during 4 days of water restriction. In both species, the soil–plant conductance, excluding stomatal conductance, declined exponentially with soil drying and was reduced to 50% above a soil water potential of −0.1 MPa, which is far from the permanent wilting point. This loss of conductance has immediate consequences for leaf water potential and the associated stomatal regulation. Both stomatal conductance and soil–plant conductance declined at a higher rate in faba bean than in maize. Estimations of the water potential at the root surface and an incomplete recovery 22 h after rewatering indicate that the loss of conductance, at least partly, occurred inside the plants, for example, through root suberization or altered aquaporin gene expression. Our findings suggest that differences in the stomatal sensitivity among plant species are partly explained by the sensitivity of root hydraulic conductance to soil drying.
Post–Affordable Care Act Improvements in Cancer Stage Among Ohio Medicaid Beneficiaries Resulted From an Increase in Stable Coverage
Authors: Koroukian Siran M. , Dong Weichuan , Albert Jeffrey M. , Kim Uriel , Eom Kirsten y. , Rose Johnie , Owusu Cynthia , Zanotti Kristine M. , Cooper Gregory S. , Tsui Jennifer 
Published: September 2022

Background:
The mechanisms underlying improvements in early-stage cancer at diagnosis following Medicaid expansion remain unknown. We hypothesized that Medicaid expansion allowed for low-income adults to enroll in Medicaid before cancer diagnosis, thus increasing the number of stably-enrolled relative to those who enroll in Medicaid only after diagnosis (emergently-enrolled).

Methods:
Using data from the 2011–2017 Ohio Cancer Incidence Surveillance System and Medicaid enrollment files, we identified individuals diagnosed with incident invasive breast (n=4850), cervical (n=1023), and colorectal (n=3363) cancer. We conducted causal mediation analysis to estimate the direct effect of pre- (vs. post-) expansion on being diagnosed with early-stage (-vs. regional-stage and distant-stage) disease, and indirect (mediation) effect through being in the stably- (vs. emergently-) enrolled group, controlling for individual-level and area-level characteristics.

Results:
The percentage of stably-enrolled patients increased from 63.3% to 73.9% post-expansion, while that of the emergently-enrolled decreased from 36.7% to 26.1%. The percentage of patients with early-stage diagnosis remained 1.3–2.9 times higher among the stably than the emergently-enrolled group, both pre-expansion and post-expansion. Results from the causal mediation analysis showed that there was an indirect effect of Medicaid expansion through being in the stably- (vs. emergently-) enrolled group [risk ratios with 95% confidence interval: 1.018 (1.010–1.027) for breast cancer, 1.115 (1.064–1.167) for cervical cancer, and 1.090 (1.062–1.118) for colorectal cancer.

Conclusion:
We provide the first evidence that post-expansion improvements in cancer stage were caused by an increased reliance on Medicaid as a source of stable insurance coverage.
Association Between Clinical Backgrounds and Malignant Progression of Suspected Intraductal Papillary Mucinous Neoplasm
Authors: Fukushima Genki , Abe Kodai , Kitago Minoru , Iwasaki Eisuke , Hirata Aya , Takemura Ryo , Ishii Ryota , Yagi Hiroshi , Abe Yuta , Hasegawa Yasushi , Fukuhara Seiichiro , Hori Shutaro , Tanaka Masayuki , Nakano Yutaka , Yokose Takahiro , Shimane Gaku , Kitagawa Yuko 
Published: September 2022

Objectives
Some intraductal papillary mucinous neoplasms (IPMNs) have malignant potential and can become pancreatic cancer. The mechanism behind the malignant progression of IPMN remains unknown. We aimed to identify the risk factors and interactions between backgrounds for IPMN.

Methods
We retrospectively enrolled 980 patients of pancreatic cancer or suspected IPMN (sIPMN) who underwent endoscopic ultrasound or retrograde cholangiopancreatography. We classified them into pancreatic cancer, high-risk sIPMN, and low-risk sIPMN, and investigated the risk factors for high-risk sIPMN.

Results
Smoking habits (odds ratio [OR], 3.74; 95% confidence interval [CI], 2.04–6.85; P < 0.001), serum carbohydrate antigen 19–9 ≥37 U/mL (OR, 6.30; 95% CI, 2.88–13.80; P < 0.001), and family history of cancers (OR, 2.38; 95% CI, 1.30–4.37; P = 0.005) were independent risk factors for high-risk suspected IPMN. Odds ratios of diabetes and neutrophil-to-lymphocyte ratio of 2.45 or greater were significantly higher in patients with a family history of cancer than those without a family history of cancer (OR, 3.28; 95% CI, 0.52–20.80 vs 1.85; 95% CI, 0.78–4.41; OR, 2.44; 95% CI, 0.81–7.34 vs 1.24; 95% CI, 0.67–2.30, respectively).

Conclusions
Understanding the interactions between background factors can effectively prevent IPMNs' malignant transformation.
Pharmacological Ascorbate Enhances Chemotherapies in Pancreatic Ductal Adenocarcinoma
Authors: O'Leary Brianne R. , Ruppenkamp Elena K. , Steers Garett J. , Du Juan , Carroll Rory S. , Wagner Brett A. , Buettner Garry R. , Cullen Joseph J. 
Published: September 2022

Objectives
Pharmacological ascorbate (P-AscH−, high-dose, intravenous vitamin C) has shown promise as an adjuvant therapy for pancreatic ductal adenocarcinoma (PDAC) treatment. The objective of this study was to determine the effects of P-AscH− when combined with PDAC chemotherapies.

Methods
Clonogenic survival, combination indices, and DNA damage were determined in human PDAC cell lines treated with P-AscH− in combination with 5-fluorouracil, paclitaxel, or FOLFIRINOX (combination of leucovorin, 5-fluorouracil, irinotecan, oxaliplatin). Tumor volume changes, overall survival, blood analysis, and plasma ascorbate concentration were determined in vivo in mice treated with P-AscH− with or without FOLFIRINOX.

Results
P-AscH− combined with 5-fluorouracil, paclitaxel, or FOLFIRINOX significantly reduced clonogenic survival in vitro. The DNA damage, measured by γH2AX protein expression, was increased after treatment with P-AscH−, FOLFIRINOX, and their combination. In vivo, tumor growth rate was significantly reduced by P-AscH−, FOLFIRINOX, and their combination. Overall survival was significantly increased by the combination of P-AscH− and FOLFIRINOX. Treatment with P-AscH− increased red blood cell and hemoglobin values but had no effect on white blood cell counts. Plasma ascorbate concentrations were significantly elevated in mice treated with P-AscH− with or without FOLFIRINOX.

Conclusions
The addition of P-AscH− to standard of care chemotherapy has the potential to be an effective adjuvant for PDAC treatment.
Prophylaxis of Post–Endoscopic Retrograde Cholangiopancreatography Pancreatitis Using Temporary Pancreatic Stents Versus Rectal Nonsteroidal Anti-inflammatory Drugs
Authors: Koshitani Tatsuya , Konaka Yoshitomo , Ohishi Takashi , Yasuda Tomoyo , Morinushi Tatsuo , Mita Masaki , Masuda Masataka , Nakano Keimei , Fuki Shuichi , Nakagawa Shuji 
Published: September 2022

Objectives
Both pancreatic stenting and rectal nonsteroidal anti-inflammatory drugs (NSAIDs) prevent post–endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis. The aim of the study was to compare post-ERCP pancreatitis (PEP) prophylaxis using pancreatic stents and/or rectal NSAIDs prospectively.

Methods
A total of 321 patients undergoing ERCP were studied. Each patient was randomly allocated to receive pancreatic stent placement (PS), 50 mg of rectal diclofenac (NSAID), or both (PS + NSAID) for PEP prophylaxis. The primary outcome was the occurrence rate of PEP, and secondary outcomes included the severity of PEP and serum pancreatic amylase and lipase levels on the day after ERCP.

Results
Five patients (PS: 2/101, NSAID: 1/106, PS + NSAID: 2/102) developed PEP, and the overall occurrence rate of PEP was 1.6% (5/309). The occurrence rates of PEP in the PS, NSAID, and PS + NSAID groups were statistically equivalent with an equivalent margin of 10%. The severity of PEP was mild in all 5 patients. Median serum pancreatic amylase and lipase levels in the NSAID group were significantly lower than those in the PS and PS + NSAID groups.

Conclusions
Rectal administration of 50 mg of diclofenac may become a first-line therapy for PEP prophylaxis in our country.
Effects of Aquatic Physical Therapy in Children With Congenital Femoral Deficiency Who Underwent Bone Lengthening Using an External Fixator: A Case Report
Authors: Castro Caio Roberto Aparecido de Paschoal , Kakihata Alessandra Mitie , Braga Douglas Martins 
Published: September 2022

Introduction and Objective:
Congenital femoral deficiency (CFD) is a malformation that affects 0.2 persons per 10,000 live births. The orthopedic treatment proposed for this disease is bone lengthening using an external fixator (EF). During this treatment, reductions in the range of motion (ROM) of the knee, alterations in the gait speed (GS), and worse quality of life (QOL) commonly occur. Therefore, rehabilitation of patients with CFD receiving this treatment is essential. Aquatic physical therapy (APT) is an innovative approach for this population, however, there are no reports on the effects of APT in patients with CFD after bone lengthening. The objective of this study was to assess the influence of APT on the knee ROM, GS, and QOL of 2 children with CFD implanted with an EF.

Case Description:
Two children with right-sided CFD implanted with an EF were selected. They received an APT protocol focusing on balance, muscle activation, analgesia and mobility of the right knee, and gait. The right knee ROM, GS, and QOL were measured using right knee goniometry, a 10-m walk test before and after each session, and the Child Health Questionnaire–Parent Form 50 before and after the protocol.

Results:
An increase in the ROM of the right knee and an improvement in the QOL were observed after the protocol. Only one of the children had an increased GS.

Conclusion:
The APT protocol increased the knee ROM and improved QOL of the 2 children with CFD implanted with an EF.
High Unreported Mortality in Children and Youth (<25 Years) Living With HIV Who Were Lost to Care From Antiretroviral Therapy Programs in Southern Africa: Results From a Multicountry Tracing Study
Authors: Nyakato Patience , Christ Benedikt , Anderegg Nanina , Muhairwe Josephine , Jefferys Laura , van Dijk Janneke , Vinikoor Michael J. , van Lettow Monique , Chimbetete Cleophas , Phiri Sam J. , Egger Matthias , Ballif Marie , Yiannoutsos Constantin T. , Schomaker Michael , Kassanjee Reshma , Davies Mary-Ann , Cornell Morna ,   on behalf of International epidemiology Databases to Evaluate AIDS Southern Africa (IeDEA-SA)
Published: September 2022

Background:
Antiretroviral therapy program mortality maybe underestimated if deceased patients are misclassified as lost.

Methods:
We used two-stage inverse probability weighting to account for probability of being: sampled for tracing and found by the tracer.

Results:
Among 680 children and youth aged <25 years on antiretroviral therapy who were lost and traced in Southern Africa between October 2017 and November 2019, estimated mortality was high at 9.1% (62/680). After adjusting for measured covariates and within-site clustering, mortality remained lower for young adults aged 20–24 years compared with infants aged <2 years [adjusted hazard ratio: 0.40 (95% confidence interval: 0.31 to 0.51)].

Conclusions:
Our study confirms high unreported mortality in children and youth who are lost and the need for tracing to assess vital status among those who are lost to accurately report on program mortality.
Dengue vaccine development: challenges and prospects
Authors: Wilder-Smith Annelies 
Published: September 2022

Purpose of review
Dengue vaccine development is a high public health priority. To date, no dengue vaccine is in widespread use. Here we review the challenges in dengue development and the latest results for the second-generation dengue vaccines.

Recent findings
The biggest hurdle is the immunological interaction between the four antigenically distinct dengue serotypes. The advantages of second-generation dengue vaccines are the inclusion of nonstructural proteins of the dengue backbone and a more convenient dosing with reduced numbers of doses needed.

Summary
Although dengue-primed individuals can already benefit from vaccination with the first licensed dengue vaccine CYD-TDV, the public health need for the dengue-naive population has not yet been met. The urgent need remains to identify correlates of both protection and enhancement; until such correlates have been identified, all second-generation dengue vaccines still need to go through full phase 3 trials. The 5-year efficacy and safety data for both second-generation dengue vaccines are imminent.
Prosthetic valve endocarditis due to Candida parapsilosis- a rare case report
Authors: Sharma Shivang , Samantaray Subhashree , Kumar Deepak , Meena Durga Shankar , Chaudhary Rahul , Jain Vidhi , Bohra Gopal Krishana , Garg Mahendra Kumar 
Published: September 2022

Fungal endocarditis is a rare and fatal condition , most frequently caused by the Candida and Aspergillus species. Fever and changing heart murmur are the most common clinical manifestations. The diagnosis of fungal endocarditis is challenging, especially that of prosthetic valve endocarditis is extremely difficult. The optimal management of the condition still remains debatable. We hereby present a case of prosthetic valve endocarditis caused by Candida parapsilosis , managed empirically with liposomal amphotericin B and later on was shifted to combination therapy with high dose echinocandin and fluconazole, but had a fatal outcome because he could not undergo timely surgical intervention. Treating Candida parapsilosis endocarditis cases are difficult because of their ability of biofilm production on native and prosthetic heart valves. A combined approach consisting of high index of clinical suspicion, early diagnosis by using serological markers followed by culture or PCR and prompt initiation of appropriate antifungals may aid in improving the outcome.
Mountains as refugia: evidence from bumble bee brain transcriptomes
Authors: Fisher Kaleigh , Duennes Michelle A. , Woodard S. Hollis 
Published: September 2022

AbstractAs anthropogenic change continues to impact global biodiversity, the importance of rapidly identifying biodiversity refugia cannot be overstated. In this study, we employed a molecular test of the hypothesis that mountains serve as refugia for bumble bees against anthropogenic stressors. To explore this hypothesis, we compared stress-related patterns of gene expression in the brains of wild, pollen-foraging bumble bees of two species, B. vosnesenskii and B. melanopygus, collected at different elevations throughout the Sierra Nevada Mountain range in California, USA. We found evidence that the expression of several immune and detoxification genes is associated with elevational differences. This suggests that bees are experiencing differential exposure to stressors along an elevational gradient, which is an important criterion for identifying refugia across dynamic and heterogenous environments. This study thus provides evidence that mountains may serve as refugia for bumble bees in response to anthropogenic stressors, as has been detected for many other organisms.
Modeling cell size regulation under complex and dynamic environments
Authors: Nieto César , Vargas-García César , Pedraza Juan Manuel , Singh Abhyudai 
Published: September 2022

AbstractIn nature, cells face changes in environmental conditions that can modify their growth rate. In these dynamic environments, recent experiments found changes in cell size regulation. Currently, there are few clues about the origin of these cell size changes. In this work, we model cell division as a stochastic process that occurs at a rate proportional to the size. We propose that this rate is zero if the cell is smaller than a minimum size. We show how this model predicts some of the properties found in cell size regulation. For example, among our predictions, we found that the mean cell size is an exponential function of the growth rate under steady conditions. We predict that cells become smaller and the way the division strategy changes during dynamic nutrient depletion. Finally, we use the model to predict cell regulation in an arbitrary complex dynamic environment.