bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti-mitochondrial Tryparedoxin Peroxidase Monoclonal Antibody-Based Immunohistochemistry for Diagnosis of Cutaneous Leishmaniasis
Authors: Freire Mariana Lourenço , Rego Felipe Dutra , Lopes Karine Ferreira , Coutinho Lucélia Antunes , Grenfell Rafaella Fortini Queiroz , Avelar Daniel Moreira , Cota Gláucia , Pascoal-Xavier Marcelo Antônio , Oliveira Edward
Published: February 2022

Cutaneous leishmaniasis (CL) remains a globally spreading public health problem. Among Latin America countries, Brazil has the greatest number of recorded CL cases with several Leishmania species being associated with human cases. Laboratory diagnosis is one of the major challenges to disease control due to the low accuracy of parasitological techniques, the restricted use of molecular techniques, and the importance of differential diagnosis with regard to several dermatological and systemic diseases. In response, we have developed and validated an immunohistochemistry (IHC) technique for CL diagnosis using anti-mTXNPx monoclonal antibody (mAb). Recombinant Leishmania–mTXNPx was produced and used as an immunogen for mAb production through the somatic hybridization technique. The viability of mAb labeling of Leishmania amastigotes was tested by IHC performed with skin biopsies from hamsters experimentally infected with Leishmania amazonensis, Leishmania braziliensis, and Leishmania guyanensis. The enzymes horseradish peroxidase (IHC-HRP) and alkaline phosphatase (IHC-AP), both biotin-free polymer detection systems, were used in the standardization step. The IHC was further validated with skin biopsies from 49 CL patients diagnosed by clinical examination and quantitative real-time polymerase chain reaction and from 37 patients presenting other dermatological infectious diseases. Other parasitological techniques, such as direct examination and culture, were also performed for confirmed CL patients. Histopathology and IHC were performed for all included patients. Overall, the highest sensitivity was observed for IHC-AP (85.7%), followed by IHC-HRP (79.6%), direct examination (77.6%), histopathological examination (HE; 65.3%), and in vitro culture (49%). Only IHC and HE presented specificity over 90% and were able to detect CL patients regardless of parasite burden (odds ratio > 1.94; 95%CI: 0.34–11.23). A significant increase in positivity rates was observed when IHC-AP was combined with direct examination (95.9%) and HE (93.9%). The IHC techniques evaluated in here detected the main Leishmania species causing CL in Brazil and can support diagnostic strategies for controlling this neglected disease, especially if used in combination with other approaches for an integrative laboratorial diagnosis.
Ecological Processes Shaping Microbiomes of Extremely Low Birthweight Infants
Authors: Zioutis Christos , Seki David , Bauchinger Franziska , Herbold Craig , Berger Angelika , Wisgrill Lukas , Berry David
Published: February 2022

The human microbiome has been implicated in affecting health outcomes in premature infants, but the ecological processes governing early life microbiome assembly remain poorly understood. Here, we investigated microbial community assembly and dynamics in extremely low birth weight infants (ELBWI) over the first 2 weeks of life. We profiled the gut, oral cavity and skin microbiomes over time using 16S rRNA gene amplicon sequencing and evaluated the ecological forces shaping these microbiomes. Though microbiomes at all three body sites were characterized by compositional instability over time and had low body-site specificity (PERMANOVA, r2 = 0.09, p = 0.001), they could nonetheless be clustered into four discrete community states. Despite the volatility of these communities, deterministic assembly processes were detectable in this period of initial microbial colonization. To further explore these deterministic dynamics, we developed a probabilistic approach in which we modeled microbiome state transitions in each ELBWI as a Markov process, or a “memoryless” shift, from one community state to another. This analysis revealed that microbiomes from different body sites had distinctive dynamics as well as characteristic equilibrium frequencies. Time-resolved microbiome sampling of premature infants may help to refine and inform clinical practices. Additionally, this work provides an analysis framework for microbial community dynamics based on Markov modeling that can facilitate new insights, not only into neonatal microbiomes but also other human-associated or environmental microbiomes.
Combined Bioremediation of Bensulfuron-Methyl Contaminated Soils With Arbuscular Mycorrhizal Fungus and Hansschlegelia zhihuaiae S113
Authors: Qian Yingying , Zhao Guoqiang , Zhou Jing , Zhao Huazhu , Mutter Thamer Y. , Huang Xing
Published: February 2022

Over the past decades, because of large-scale bensulfuron-methyl (BSM) application, environmental residues of BSM have massively increased, causing severe toxicity in rotation-sensitive crops. The removal of BSM from the environment has become essential. In this study, the combined bioremediation of the arbuscular mycorrhizal fungi (AMF) Rhizophagus intraradices and BSM-degrading strain Hansschlegelia zhihuaiae S113 of BSM-polluted soil was investigated. BSM degradation by S113 in the maize rhizosphere could better promote AMF infection in the roots of maize, achieving an infection rate of 86.70% on the 36th day in the AMF + S113 + BSM group. Similarly, AMF enhanced the colonization and survival of S113 in maize rhizosphere, contributing 4.65 × 105 cells/g soil on the 15th day and 3.78 × 104 cells/g soil on the 20th day to a population of colonized-S113 (based possibly on the strong root system established by promoting plant-growth AMF). Both S113 and AMF coexisted in rhizosphere soil. The BSM-degrading strain S113 could completely remove BSM at 3 mg/kg from the maize rhizosphere soil within 12 days. AMF also promoted the growth of maize seedlings. When planted in BSM-contaminated soil, maize roots had a fresh weight of 2.59 ± 0.26 g in group S113 + AMF, 2.54 ± 0.20 g in group S113 + AMF + BSM, 2.02 ± 0.16 g in group S113 + BSM, and 2.61 ± 0.25 g in the AMF group, all of which exceeded weights of the control group on the 36th day except for the S113 + BSM group. Additionally, high-throughput sequencing results indicated that simultaneous inoculation with AMF and strain S113 of BSM-polluted maize root-soil almost left the indigenous bacterial community diversity and richness in maize rhizosphere soil unaltered. This represents a major advantage of bioremediation approaches resulting from the existing vital interactions among local microorganisms and plants in the soil. These findings may provide theoretical guidance for utilizing novel joint-bioremediation technologies, and constitute an important contribution to environmental pollution bioremediation while simultaneously ensuring crop safety and yield.
The Disease Modification Conundrum in Parkinson’s Disease: Failures and Hopes
Authors: Mari Zoltan , Mestre Tiago A.
Published: February 2022

In the last half-century, Parkinson’s disease (PD) has played a historical role in demonstrating our ability to translate preclinical scientific advances in pathology and pharmacology into highly effective clinical therapies. Yet, as highly efficacious symptomatic treatments were successfully developed and adopted in clinical practice, PD remained a progressive disease without a cure. In contrast with the success story of symptomatic therapies, the lack of translation of disease-modifying interventions effective in preclinical models into clinical success has continued to accumulate failures in the past two decades. The ability to stop, prevent or mitigate progression in PD remains the “holy grail” in PD science at the present time. The large number of high-quality disease modification clinical trials in the past two decades with its lessons learned, as well as the growing knowledge of PD molecular pathology should enable us to have a deeper understanding of the reasons for past failures and what we need to do to reach better outcomes. Periodic reviews and mini-reviews of the unsolved disease modification conundrum in PD are important, considering how this field is rapidly evolving along with our views and understanding of the possible explanations.
Low Serum Superoxide Dismutase Is Associated With a High Risk of Cognitive Impairment After Mild Acute Ischemic Stroke
Authors: Zhang Ming-Si , Liang Jian-Hai , Yang Meng-Jia , Ren Yue-Ran , Cheng Dai-Hong , Wu Qi-Heng , He Yan , Yin Jia
Published: February 2022

Background

Post-stroke cognitive impairment (PSCI) is a common complication after stroke, but effective therapy is limited. Identifying potential risk factors for effective intervention is warranted. We investigated whether serum superoxide dismutase (SOD) levels were related to cognitive impairment after mild acute ischemic stroke (AIS) by using a prospective cohort design.

Methods

A total of 187 patients diagnosed with mild AIS (National Institutes of Health Stroke Scale ≤ 8) were recruited. Serum SOD, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and interleukin-6 (IL-6) levels were measured, and cognitive assessments (Mini-Mental State Examination, MMSE; Montreal Cognitive Assessment, MoCA) were performed in the early phase (within 2 weeks). These indexes and assessments were repeated at 3 months after onset. MoCA < 22 was defined as early cognitive impairment (CI-E) within 2 weeks and late cognitive impairment (CI-L) at 3 months after stroke.

Results

In a survey, 105 of 187 (56.1%) patients were identified as CI-E after mild AIS. Lower serum SOD associated with higher inflammatory biomarkers (ESR, CRP, and IL-6) and worse cognitive scores was observed in CI-E patients. In a survey, 39 of 103 (37.9%) stroke patients who completed the 3-month follow-up were identified as CI-L. Serum SOD was consistently lower in CI-L patients at baseline and 3 months and positively associated with cognitive scores. In adjusted analyses, low serum SOD at baseline was independently associated with high risks of CI-E and CI-L, with odds ratios (ORs) of 0.64 and 0.33 per standard deviation increase in serum SOD, respectively. Multiple-adjusted spline regression models showed linear associations between serum SOD and CI-E (P = 0.044 for linearity) and CI-L (P = 0.006 for linearity). Moreover, 35.2% (19/54) of CI-E patients cognitively recovered during the 3-month follow-up. In multivariable analysis, SOD was identified as a protective factor for cognitive recovery after stroke (OR 1.04, 95% CI: 1.01–1.08, P = 0.024).

Conclusion

We demonstrate that low serum SOD is associated with a high risk of cognitive impairment after mild AIS, indicating SOD may be a potential modifiable factor for PSCI.
Clinical, Neurophysiological, and Genetic Predictors of Recovery in Patients With Severe Acquired Brain Injuries (PRABI): A Study Protocol for a Longitudinal Observational Study
Authors: Hakiki Bahia , Donnini Ida , Romoli Anna Maria , Draghi Francesca , Maccanti Daniela , Grippo Antonello , Scarpino Maenia , Maiorelli Antonio , Sterpu Raisa , Atzori Tiziana , Mannini Andrea , Campagnini Silvia , Bagnoli Silvia , Ingannato Assunta , Nacmias Benedetta , De Bellis Francesco , Estraneo Anna , Carli Valentina , Pasqualone Eugenia , Comanducci Angela , Navarro Jorghe , Carrozza Maria Chiara , Macchi Claudio , Cecchi Francesca
Published: February 2022

Background

Due to continuous advances in intensive care technology and neurosurgical procedures, the number of survivors from severe acquired brain injuries (sABIs) has increased considerably, raising several delicate ethical issues. The heterogeneity and complex nature of the neurological damage of sABIs make the detection of predictive factors of a better outcome very challenging. Identifying the profile of those patients with better prospects of recovery will facilitate clinical and family choices and allow to personalize rehabilitation. This paper describes a multicenter prospective study protocol, to investigate outcomes and baseline predictors or biomarkers of functional recovery, on a large Italian cohort of sABI survivors undergoing postacute rehabilitation.

Methods

All patients with a diagnosis of sABI admitted to four intensive rehabilitation units (IRUs) within 4 months from the acute event, aged above 18, and providing informed consent, will be enrolled. No additional exclusion criteria will be considered. Measures will be taken at admission (T0), at three (T1) and 6 months (T2) from T0, and follow-up at 12 and 24 months from onset, including clinical and functional data, neurophysiological results, and analysis of neurogenetic biomarkers.

Statistics

Advanced machine learning algorithms will be cross validated to achieve data-driven prediction models. To assess the clinical applicability of the solutions obtained, the prediction of recovery milestones will be compared to the evaluation of a multiprofessional, interdisciplinary rehabilitation team, performed within 2 weeks from admission.

Discussion

Identifying the profiles of patients with a favorable prognosis would allow customization of rehabilitation strategies, to provide accurate information to the caregivers and, possibly, to optimize rehabilitation outcomes.

Conclusions

The application and validation of machine learning algorithms on a comprehensive pool of clinical, genetic, and neurophysiological data can pave the way toward the implementation of tools in support of the clinical prognosis for the rehabilitation pathways of patients after sABI.
Late-Onset Focal Epilepsy: Electroclinical Features and Prognostic Role of Leukoaraiosis
Authors: Tartara Elena , Micalizzi Elisa , Scanziani Sofia , Ballante Elena , Paoletti Matteo , Galimberti Carlo Andrea
Published: February 2022

The aim of this study was to describe the electroclinical and prognostic characteristics, and to investigate the role of leukoaraiosis in outpatients with new-onset elderly focal epilepsy aged ≥60 years, referred to a tertiary epilepsy center between 2005 and December 31, 2020. Among the 720 patients who were referred to the center, we retrospectively selected 162 consecutive outpatients, with a first referral for recent-onset focal epilepsy of unknown cause (UC) or structural cause (SC), and collected a clinical and standard-Electroencephalogram (S-EEG), 24-h ambulatory EEG (A-EEG), and neuroimaging data. We also analyzed the seizure prognosis after titration of the first antiseizure medication (ASM). One hundred and four UC and 58 SC patients, followed up for 5.8 ± 5.3 years (mean ± SD), were included. Compared with the SC group, the patients with UC showed a predominance of focal seizures with impaired awareness (51.9% of cases) and focal to bilateral tonic-clonic seizures during sleep (25%); conversely, the SC group, more frequently, had focal to bilateral tonic-clonic seizures during wakefulness (39.6%) and focal aware seizures (25.8%) (p < 0.0001). Oral or gestural automatisms were prevalent in UC epilepsy (20.2 vs. 6.9% in the SC group, p = 0.04). In UC compared to patients with SC, interictal epileptiform discharges showed a preferential temporal lobe localization (p = 0.0007), low expression on S-EEG, and marked activation during deep Non-Rapid Eye Movement (NREM) sleep (p = 0.003). An overall good treatment response was found in the whole sample, with a probability of seizure freedom of 68.9% for 1 year. The cumulative probability of seizure freedom was significantly higher in the UC compared with the SC group (p < 0.0001). The prognosis was worsened by leukoaraiosis (p = 0.012). In the late-onset focal epilepsy of unknown cause, electroclinical findings suggest a temporal lobe origin of the seizures. This group showed a better prognosis compared with the patients with structural epilepsy. Leukoaraiosis, per se, negatively impacted on seizure prognosis.
Water Diffusivity Changes Along the Perivascular Space After Lumboperitoneal Shunt Surgery in Idiopathic Normal Pressure Hydrocephalus
Authors: Kikuta Junko , Kamagata Koji , Taoka Toshiaki , Takabayashi Kaito , Uchida Wataru , Saito Yuya , Andica Christina , Wada Akihiko , Kawamura Kaito , Akiba Chihiro , Nakajima Madoka , Miyajima Masakazu , Naganawa Shinji , Aoki Shigeki
Published: February 2022

Background

The aim of this study was to evaluate the water diffusivity changes along the perivascular space after lumboperitoneal shunt (LPS) surgery in idiopathic normal pressure hydrocephalus.

Methods

Nine patients diagnosed with idiopathic normal pressure hydrocephalus (iNPH; three men and six women, mean age ± SD = 75.22 ± 5.12 years) according to the guidelines for iNPH in Japan were included in the study. Post-LPS surgery, six patients with iNPH who exhibited improvement in symptoms were defined as responder subjects, while three patients with iNPH who did not were defined as non-responder subjects. We calculated the mean analysis along the perivascular space (ALPS) index of the left and right hemispheres and compared the differences between pre- and post-LPS surgery mean ALPS indices in iNPH patients. In the responder or non-responder subjects, the mean ALPS indices in the pre- and post-operative iNPH groups were compared using Wilcoxon signed-rank tests. Next, correlation analyses between pre- and post-operation changes in the mean ALPS index and clinical characteristics were conducted.

Results

The mean ALPS index of the post-operative iNPH group was significantly higher than that of the pre-operative iNPH group (p = 0.021). In responder subjects, the mean ALPS index of the post-operative iNPH group was significantly higher than that of the pre-operative iNPH group (p = 0.046). On the other hand, in the non-responder subjects, the mean ALPS index of the post-operative iNPH group was not significantly different compared to the pre-operative iNPH group (p = 0.285). The mean ALPS index change was not significantly correlated with changes in the Mini-Mental State Examination (MMSE) score (r = −0.218, p = 0.574), Frontal Assessment Battery (FAB) score (r = 0.185, p = 0.634), Trail Making Test A (TMTA) score (r = 0.250, p = 0.516), and Evans' index (r = 0.109, p = 0.780). In responder subjects, the mean ALPS index change was significantly correlated with Evans' index in pre-operative patients with iNPH (r = 0.841, p = 0.036).

Conclusion

This study demonstrates the improved water diffusivity along perivascular space in patients with iNPH after LPS surgery. This could be indicative of glymphatic function recovery following LPS surgery.
Acute Medication Use in Patients With Migraine Treated With Monoclonal Antibodies Acting on the CGRP Pathway: Results From a Multicenter Study and Proposal of a New Index
Authors: Sette Lucia , Caponnetto Valeria , Ornello Raffaele , Nežádal Tomáš , Čtrnáctá Dana , Šípková Jitka , Matoušová Zuzana , Sacco Simona
Published: February 2022

Introduction

Assessing the impact of migraine preventive treatments on acute medication consumption is important in clinical evaluation. The number of acute medication intakes per each monthly migraine day (MMD) could provide insights on migraine burden and represent a new proxy of treatment effectiveness in clinical trials and real-life studies. We evaluated the effect of monoclonal antibodies acting on calcitonin gene-related peptide (CGRP) pathway on the consumption of migraine acute medication in real-life.

Methods

In two headache centers in Prague (CZ), we included and followed up to 6 months consecutive patients treated with MoAbs acting on CGRP (erenumab or fremanezumab). For each month of treatment, we reported monthly drug intake (MDI) in doses of any medication, migraine-specific (MS), and non-migraine-specific (non-MS) medications, and computed a ratio between MMDs and MDI, i.e., Migraine Medication Index (MMI) for MS and non-MS medications.

Results

We included 90 patients (91.1% women) with a median age of 47 [interquartile range (IQR) 42–51] years; 81 (90.0%) treated with erenumab and 9 (10.0%) with fremanezumab. Median MMDs decreased from 11 (IQR 8–14) at baseline to 4 (IQR 2–5) at Month 3 (p < 0.001 vs. baseline) and 3 (IQR 2–6) at Month 6 (p < 0.001 vs. baseline). Median MDI decreased from 15 drug intakes (IQR 11–20) at baseline to four drug intakes (IQR 2–7) at Month 3 (p < 0.001) and four drug intakes (IQR 2–7) at Month 6 (p < 0.001).The corresponding MDIs for MS medications were 10 (IQR 6–14) at baseline, 3 (IQR 1–5, p < 0.001) at Month 3, and 2 (IQR 0–4, p < 0.001) at Month 6. Monthly drug intakes for non-MS medications were 4 (IQR 0–9) at baseline, 1 (IQR 0–3, p < 0.001) at Month 3 and at Month 6.Median MMI decreased from 1.32 (IQR 1.11–1.68) at baseline to 1.00 (IQR 1.00–1.50, p < 0.001) at Month 3 and 1.00 (IQR 1.00–1.34, p < 0.001) at Month 6.

Conclusions

We confirmed that MoAbs acting on CGRP pathway decrease acute migraine medication consumption. We proposed a new index that can be easily applied in clinical practice to quantify migraine burden and its response to acute medication. Our index could help optimizing migraine acute treatment in clinical practice.
Integrative Treatment for Tinnitus Combining Repeated Facial and Auriculotemporal Nerve Blocks With Stimulation of Auditory and Non-auditory Nerves
Authors: Sirh Soo Ji , Sirh So Woon , Mun Hah Yong , Sirh Heon Man
Published: February 2022

Background

Tinnitus is a prevalent condition (>10% of the population) affecting the quality of life of 0.5–3% of the population. Although several treatments have been proposed, most of these lack evidence of efficacy in the treatment of chronic tinnitus. Thus, we aimed to evaluate an integrative treatment strategy for subacute and chronic tinnitus.

Methods

This retrospective chart review study included 55 patients with tinnitus (subacute, n = 15; chronic, n = 40) who underwent repeated nerve blocks after stimulation of the trigeminal (V) and facial (VII) nerves to modulate the auditory and non-auditory nervous systems via the vestibulocochlear (VIII) cranial nerve pathways. We used a simplified smiley tinnitus-visual analog scale (T-VAS) with scores ranging from 0 to 10 combining the effect of tinnitus loudness, distress, and quality of life as the outcome measure to evaluate the efficacy of our treatment method. Statistical analyses were performed using SPSS (version 18.0, SPSS Inc., Chicago, IL, United States), one-way and two-way analysis of variance.

Results

In more than 87.5% of patients (14/15 subacute, 35/40 chronic), tinnitus disappeared or had significantly reduced by the end of the treatment. The mean T-VAS score reduced significantly from 7.13 to 0.60 in the subacute group and from 7.73 to 1.53 in the chronic group by the end of treatment (p < 0.05). The benefits were maintained after treatment cessation and at the 1-year follow-up. The average number of treatment procedures was 9.8 ± 3.589 (range, 5–15) in the subacute group and 9.775 ± 3.717 (range, 5–18) in the chronic group.

Conclusion

Our results show that the proposed integrative approach is highly effective in treating subacute and chronic tinnitus and represents a promising therapeutic approach.
Conventional Ultrasound and Contrast-Enhanced Ultrasound in Hepatic Epithelioid Hemangioendothelioma: Retrospective Evaluation in 20 Cases
Authors: Qiu Tingting , Zhu Dongmei , Fu Rong , Luo Yan , Ling Wenwu
Published: February 2022

Objectives

This study aimed to analyze the patterns of conventional ultrasound (CUS) and contrast-enhanced ultrasound (CEUS) in 20 patients with diagnosis of hepatic epithelioid hemangioendothelioma (HEHE).

Methods

Twenty patients (12 females and 8 males) with mean age of 43.6 ± 13.6 years were included in this study from January 2012 to May 2020. CUS, CEUS, computed tomography (CT) and magnetic resonance imaging (MRI) features of the twenty patients with histologically proven HEHE were retrospectively reviewed by two radiologists. The clinical manifestations and the pathological findings of all patients with HEHE are described.

Results

There were 3 types of HEHE in imaging, including single nodular (8/20, 40%), multifocal nodular (10/20, 50%), and diffuse type (2/20, 10%). The mean size of lesions was 4.2 ± 2.6 cm. B-mode ultrasound of HEHE showed hypoechoic (15/20, 75%), heterogeneous echogenicity (4/20, 20%), or hyperechoic (1/20, 5%) lesions with regular shape (18/20, 90%) near the liver capsule (17/20, 85%), and occasionally with a halo (4/20, 20%) and calcifications (3/20, 15%). Eight out of the 20 patients also had CEUS. On CEUS, HEHE demonstrated peripheral rim-like (5/8, 62.5%), heterogeneous (2/8, 25%), or homogeneous (1/8, 12.5%) hyperenhancement in the arterial phase. All patients (8/8, 100%) showed hypoenhancement in the portal and late phase. CEUS detected more lesions than CUS in 3 patients (3/8, 37.5%). In addition, central irregular unenhanced zones were observed in 6 patients (6/8, 75%). On contrast-enhanced CT or MRI, most cases presented with capsule retraction sign and lollipop sign.

Conclusions

HEHE demonstrated specific findings on ultrasound, which includes multifocal hypoechoic lesions in a subcapsular distribution with typical enhancement characteristics of malignant hepatic tumors.
The Prognoses of Young Women With Breast Cancer (≤35 years) With Different Surgical Options: A Propensity Score Matching Retrospective Cohort Study
Authors: Li Pei , Li Lun , Xiu Bingqiu , Zhang Liyi , Yang Benlong , Chi Yayun , Xue Jingyan , Wu Jiong
Published: February 2022

Background

Compared with older patients, young women with breast cancer (YWBCs) have a poorer prognosis and a higher risk of recurrence. Ages ≤35 years are independent risk factors for local recurrence of breast cancer. Surgery is the most important local treatment for YWBC, and there is still a lack of prospective studies comparing surgical options for recurrence and survival. We retrospectively compared the effects of surgical options on disease-free survival (DFS) and overall survival (OS) of YWBC at Fudan University Shanghai Cancer Center (FUSCC).

Methods

YWBCs (age ≤35 years) who underwent surgery at FUSCC between 2008 and 2016 were retrospectively analyzed and divided into three groups according to surgical options: 1) breast-conserving surgery (BCS), 2) mastectomy alone (M), and 3) mastectomy with reconstruction (RECON). The DFS and OS outcome rates from the three surgical options were compared using the Kaplan–Meier method and Cox regression model. Propensity score matching (PSM) was also used to balance the baseline characteristics to eliminate selection bias.

Results

A total of 1,520 YWBCs were enrolled with a median follow-up of 5.1 years, including 524 patients (34.5%) who underwent BCS, 676 patients (44.5%) who underwent M, and 320 patients (21.1%) who underwent RECON. The 5-year DFS rates were 96%, 87%, and 93%, respectively (P < 0.001); the 5-year OS rates were 98%, 94%, and 97%, respectively (P = 0.002). Multivariate Cox analysis showed that DFS and OS were significantly improved in patients undergoing BCS compared with those undergoing M, with hazard ratios (HR) of 0.448 (95% CI 0.276–0.728; P = 0.001) and 0.405 (95% CI 0.206–0.797, P = 0.009), respectively. After PSM, DFS and OS rates were significantly improved in patients undergoing BCS compared to patients undergoing M (DFS, P = 0.001; OS, P = 0.009); RECON was also improved compared to patients undergoing M in terms of DFS and OS, but the difference was not statistically significant (DFS, P = 0.164; OS, P = 0.130).

Conclusions

The surgical options were independent factors affecting DFS and OS in YWBC, and the DFS and OS rates were significantly improved in the BCS group compared to those in the M group. BCS is preferred for early YWBC, and RECON is the best option for remodeling the body images of YWBC who do not have breast-conserving conditions.
Cytokine Profiles of Head and Neck Squamous Cell Carcinoma Undergoing Dual Immunotherapy With Cetuximab and Pembrolizumab Identify Interferon Gamma-Induced Protein 10 as Novel Biomarker
Authors: Berszin Michael , Michaelides Ioannis , Siemert Julia , Röhl Louisa , Wellhausen Jana , Wald Theresa , Bohr Christopher , Künzel Julian , Gradistanac Tanja , Dietz Andreas , Zebralla Veit , Pirlich Markus , Wiegand Susanne , Wichmann Gunnar
Published: February 2022

Background

Pembrolizumab and cetuximab are antibodies under investigation in head and neck squamous cell carcinoma (HNSCC) either as single agents or combined with cisplatin and other chemotherapeutic drugs, e.g., 5-fluorouracil and/or docetaxel. However, also the combination of both antibodies may have potential in recurrent/metastatic (R/M) HNSCC, in particular in cisplatin-resistant or -refractory cases or patients with comorbid disease, e.g. patients with impaired renal function.

Methods

To clarify potential benefit that may result from such combination, we used the FLAVINO assay, a short-time ex vivo assay to compare responsiveness of HNSCC to pembrolizumab, cetuximab and both combined regarding colony formation of epithelial cells of biopsy-derived tumor samples and their cytokine production within three days either without or with stimulation with 10 ng/mL interferon gamma (IFN-γ). Vascular endothelial growth factor A (VEGF), monocyte chemoattractant protein 1 (MCP-1 or CCL2), interleukin 6 (IL-6), IL-8, IFN-γ, and interferon gamma-induced protein 10 (IP-10 or CXCL10) in supernatants were measured by ELISA.

Results

We detected huge heterogeneity in response to cetuximab, pembrolizumab and both combined with and without IFN-γ stimulation. Moreover, we detected a link between IFN-γ induced IP-10 release and improved outcome in those HNSCC patients who were capable to respond to IFN-γ and pembrolizumab, cetuximab and both combined with a further increase in IP-10 production. We derived an “IP-10 score” that independent from clinical characteristics of HNSCC patients and therapy regimens applied was able to predict their outcome.

Conclusions

The heterogeneity in the ex vivo response of cetuximab, pembrolizumab and both combined with and without IFN-γ stimulation identifies subgroups of HNSCC patients with deviating OS.
Incorporation of PET Metabolic Parameters With Clinical Features Into a Predictive Model for Radiotherapy-Related Esophageal Fistula in Esophageal Squamous Cell Carcinoma
Authors: Li Kaixin , Ni XiaoLei , Lin Duanyu , Li Jiancheng
Published: February 2022

Purpose

To determine whether the addition of metabolic parameters from fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scans to clinical factors could improve risk prediction models for radiotherapy-related esophageal fistula (EF) in esophageal squamous cell carcinoma (ESCC).

Methods and Materials

Anonymized data from 185 ESCC patients (20 radiotherapy-related EF-positive cases) were collected, including pre-therapy PET/CT scans and EF status. In total, 29 clinical features and 15 metabolic parameters from PET/CT were included in the analysis, and a least absolute shrinkage and selection operator logistic regression model was used to construct a risk score (RS) system. The predictive capabilities of the models were compared using receiver operating characteristic (ROC) curves.

Results

In univariate analysis, metabolic tumor volume (MTV)_40% was a risk factor for radiotherapy (RT)-related EF, with an odds ratio (OR) of 1.036 [95% confidence interval (CI): 1.009–1.063, p = 0.007]. However, it was excluded from the predictive model using multivariate logistic regression. Predictive models were built based on the clinical features in the training cohort. The model included diabetes, tumor length and thickness, adjuvant chemotherapy, eosinophil count, and monocyte-to-lymphocyte ratio. The RS was defined as follows: 0.2832 − (7.1369 × diabetes) + (1.4304 × tumor length) + (2.1409 × tumor thickness) – [8.3967 × adjuvant chemotherapy (ACT)] − (28.7671 × eosinophils) + (8.2213 × MLR). The cutoff of RS was set at −1.415, with an area under the curve (AUC) of 0.977 (95% CI: 0.9536–1), a specificity of 0.929, and a sensitivity of 1. Analysis in the testing cohort showed a lower AUC of 0.795 (95% CI: 0.577–1), a specificity of 0.925, and a sensitivity of 0.714. Delong’s test for two correlated ROC curves showed no significant difference between the training and testing sets (p = 0.109).

Conclusions

MTV_40% was a risk factor for RT-related EF in univariate analysis and was screened out using multivariate logistic regression. A model with clinical features can predict RT-related EF.
A Novel Risk Defining System for Pediatric T-Cell Acute Lymphoblastic Leukemia From CCCG-ALL-2015 Group
Authors: Liu Xiaoming , Zou Yao , Zhang Li , Guo Ye , Chen Yumei , Yang Wenyu , Chen Xiaojuan , Wang Shuchun , Zhang Yingchi , Ruan Min , Chang Lixian , Zhang Xiaoyan , Zhao Beibei , Zhang Ranran , Zhang Aoli , Liu Lipeng , Zhang Luyang , Yi Meihui , Zhu Xiaofan
Published: February 2022

Objective

T-cell acute lymphoblastic leukemia (T-ALL) is a rare hematological malignancy with a poor prognosis. The present study aims to identify the precise risk grouping of children with T-ALL.

Methods

We analyzed the outcomes for 105 consecutive patients treated using the Chinese Children’s Cancer Group ALL-2015 (CCCG-ALL-2015) protocol registered with the Chinese Clinical Trial Registry (ChiCTR-IPR-14005706) between 2015 and 2020 in our center. Nine out of 21 clinical and biological indicators were selected for the new scoring system based on the analysis in this study.

Results

The 5-year overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) rates for the 105 patients were 83.1 ± 4.8%, 72.4 ± 5.6%, and 78.4 ± 3.6%, respectively. Based on the new scoring system, 90 evaluable children were regrouped into low-risk (n=22), intermediate-risk (n=50), and high-risk (n=18) groups. The 5-year survival (OS, EFS, and RFS) rates for all patients in the low-risk group were 100%, significantly higher than the rates for those in the intermediate-risk group (91.2 ± 5.2%, 74.4 ± 8.6%, and 82.5 ± 6.2%, respectively) and high-risk group (59.0 ± 13.2%, 51.9 ± 12.4%, and 51.9 ± 12.4%, respectively) (all P values < 0.01).

Conclusion

The CCCG-ALL-2015 program significantly improved the treatment outcomes for childhood T-ALL as compared with the CCCG-ALL-2008 protocol. Our new refined risk grouping system showed better stratification among pediatric T-ALL patients and better potential in evaluating therapeutic efficacy.
Integrative Analysis of a Pyroptosis-Related Signature of Clinical and Biological Value in Multiple Myeloma
Authors: Wang Huizhong , Shao Ruonan , Lu Shujing , Bai Shenrui , Fu Bibo , Lai Renchun , Lu Yue
Published: February 2022

Purpose

Pyroptosis is an inflammation-based programmed cell death that holds great potential as a novel cancer therapeutic target in patients with multiple myeloma (MM). However, thus far, the function of pyroptosis-related genes (PRGs) in MM and their prognostic relevance remains undetermined.

Methods

The model was established by the LASSO analysis, based on the Gene Expression Omnibus (GEO) dabatase, and its efficacy was verified using two external datasets. The model’s predictive ability was assessed by the Kaplan-Meier survival and time-dependent receiver operating characteristic (ROC) curves. Finally, a nomogram was established for clinical application. We also confirmed the validity of our model using specimens and in vitro experiments.

Results

We established an 11-PRG signature profile, and verified its efficacy using two validation cohorts (VCs). In both cohorts, patients were separated into two subpopulations, according to their median risk scores (RS). Our analysis revealed that high-risk (HR) patients experienced considerably lower overall survival (OS), compared to the low-risk (LR) patients. Using functional enrichment and immune infiltration analyses, we demonstrated that the immunologic status was strongly related to RS. Furthermore, using a pyroptosis inhibitor Q-VD-OPh, we revealed that MM cell proliferation and progression was drastically suppressed and the doxorubicin (DOX)-induced apoptosis was reversed.

Conclusion

Based on our analysis, pyroptosis not only serves as a measure of MM treatment efficiency and patient prognosis, but is also a possible target for anti-MM therapy.
The Association Between Alveolar Dead Space Fraction and Mortality in Pediatric Acute Respiratory Distress Syndrome: A Prospective Cohort Study
Authors: Oh Sheow Boon , Aguilan Apollo , Tan Herng Lee , Ma Yi-Jyun , Sultana Rehena , Lee Jan Hau , Wong Judith Ju Ming
Published: February 2022

Background

Alveolar dead-space fraction (AVDSF), the volume of alveolar gas that does not participate in gas exchange, has been reported to predict mortality and morbidity in adults with acute respiratory distress syndrome (ARDS). This study aims to characterize AVDSF in patients with pediatric ARDS (PARDS), to determine its association with clinical outcomes and examine the validity of a previously studied cutoff (AVDSF > 0.25).

Methods

This was a prospective cohort study performed in the setting of a lung protective mechanical ventilation protocol. AVDSF was calculated by the equation: AVDSF = [partial pressure of arterial carbon dioxide (PaCO2) – end tidal carbon dioxide (etCO2)]/PaCO2. Receiver operating curve and Youden index were used to identify an AVDSF cutoff associated with mortality, which characterized “high or low AVDSF” groups. Correlation between AVDSF and clinical indices of severity were determined [including daily oxygenation index (OI), admission Pediatric Index of Mortality 2 (PIM 2) and Pediatric Logistic Organ Dysfunction (PELOD) scores]. The primary outcome, mortality in PARDS patients, was compared between the high and low AVDSF groups and analyzed in a multivariable logistic regression adjusting for inotrope use and PIM 2 score. Secondary outcomes included 28-day ventilator-free (VFD) and intensive care unit-free (IFD) days.

Results

Sixty-nine PARDS patients with a median (interquartile range) age of 4.5 (0.8, 10.6) years were included in this analysis. Daily AVDSF correlated with daily OI (R2 = 0.10; p < 0.001). Mean AVDSF over the first 7 days of PARDS correlated with PIM 2 (R2 = 0.10; p = 0.010) and PELOD (R2 = 0.12; p = 0.004) scores. The greatest area under the curve identified an AVDSF cutoff of 0.22, which was close to the previously suggested 0.25. The high AVDSF group had higher mortality [7/19 (36.8%) vs. 5/50 (10.0%); p = 0.009] and lower VFD [2 (0, 18) vs. 21 (15, 24); p = 0.007] and IFD [0 (0, 16) vs. 16 (5, 21); p = 0.013]. In the multivariable model, being in the high AVDSF group [adjusted odds ratio 4.67 (95% CI: 1.12, 19.39)] was significantly associated with mortality.

Conclusions

High AVDSF was independently associated with increased mortality and decreased VFD and IFD. AVDSF may be complementary to oxygenation indices in risk stratifying PARDS and warrant further study.
The TCM Preparation Feilike Mixture for the Treatment of Pneumonia: Network Analysis, Pharmacological Assessment and Silico Simulation
Authors: Peng Juqin , Chen Xiaoxiao , Hou Min , Yang Kuo , Yang Bing , Wang Pan , Du Yang , Yu Qingyuan , Ren Junguo , Liu Jianxun
Published: February 2022

The Feilike mixture (FLKM) is a valid prescription that is frequently used to assist in the clinical treatment of pneumonia. However, the mechanisms of its effects remain unclear. First, through literature evaluation, it was preliminarily determined that FLKM improved clinical symptoms, regulated immune inflammation response and ameliorated pulmonary function. Then, via database search and literature mining, 759 targets of the 104 active compounds of FLKM were identified. The component-target (CT) network showed that the key active compositions were resveratrol, stigmasterol, beta-sitosterol, sesamin, and quercetin. 115 targets overlapped with pneumonia-related targets. The protein-protein interaction (PPI) network identified TNF, AKT1, IL6, JUN, VEGFA and MAPK3 as hub targets. KEGG analyses found that they were mainly enriched in immune related pathway. Next, in vivo experiment, we observed that FLKM ameliorated pathological injury of lung tissue and reduced neutrophil infiltration in rats with LPS-induced pneumonia. And FLKM decreased the concentration of TNF-α and IL-6 in BALF and downregulated the expression of p38MAPK, AKT and VEGFA in lung tissue. Finally, Molecular docking tests showed tight docking of these predicted targeted proteins with key active compounds. Molecular dynamics simulation was employed to assess stability and flexibility of receptor-ligand. Among them, AKT1- stigmasterol bound more stably, and their binding free energies were −47.91 ± 1.62 kcal/mol. This study revealed core compositions and targets for FLKM treating pneumonia and provided integrated pharmacological evidence to support its clinical efficacy.
Toxicity of Tetradium ruticarpum: Subacute Toxicity Assessment and Metabolomic Identification of Relevant Biomarkers
Authors: Shan Qiyuan , Tian Gang , Han Xin , Hui Hui , Yamamoto Mai , Hao Min , Wang Jingwei , Wang Kuilong , Sang Xianan , Qin Luping , Chen Guanqun , Cao Gang
Published: February 2022

Tetradium ruticarpum (TR) is widely used in Asia to treat gastrointestinal disorders and pain. Stir-frying with licorice aqueous extract is a traditional processing procedure of TR formed in a long-term practice and performed before clinical application, and believed to reduce TR’s toxicity. However, its toxicity and possible toxicity attenuation approach are yet to be well investigated. Subacute toxicity and metabolomics studies were conducted to help understand the toxicity of TR. The subacute toxicity assessment indicated that 3 fold of the recommended therapeutic dose of TR did not show obvious subacute toxicity in rats. Although an extremely high dose (i.e., 60 fold of the recommended dose) may cause toxicity in rats, it reversed to normal after 2 weeks of recovery. Hepatocellular injury was the major toxic phenotype of TR-induced liver damage, indicating as aspartate aminotransferase (AST) and liver index increasing, with histopathologic findings as local hepatocyte necrosis, focal inflammatory cell infiltration, slightly bile duct hyperplasia, and partial hepatocyte vacuolation. Moreover, we evaluated the impact of processing in toxicity. TR processed with licorice could effectively reduce drug-induced toxicity, which is a valuable step in TR pretreatment before clinical application. Metabolomics profiling revealed that primary bile acid biosynthesis, steroid biosynthesis, and arachidonic acid metabolism were mainly involved in profiling the toxicity metabolic regulatory network. The processing procedure could back-regulate these three pathways, and may be in an Aryl hydrocarbon Receptor (AhR) dependent manner to alleviate the metabolic perturbations induced by TR. 7α-hydroxycholesterol, calcitriol, and taurocholic acid were screened and validated as the toxicity biomarkers of TR for potential clinical translation. Overall, the extensive subacute toxicity evaluation and metabolomic analysis would not only expand knowledge of the toxicity mechanisms of TR, but also provide scientific insight of traditional processing theory, and support clinical rational use of TR.
Berberine Inhibits the Adhesion of Candida albicans to Vaginal Epithelial Cells
Authors: Zhao Ting , Zhang Kang , Shi Gaoxiang , Ma Kelong , Wang Benfan , Shao Jing , Wang Tianming , Wang Changzhong
Published: February 2022

Vulvovaginal candidiasis (VVC) is an inflammatory disease of the vagina mainly caused by Candida albicans (C. albicans), which affects around three-quarters of all women during their reproductive age. Although some antifungal drugs such as azoles have been applied clinically for many years, their therapeutic value is very limited due to the emergence of drug-resistant strains. Previous studies have shown that the adhesion of C. albicans to vaginal epithelial cells is essential for the pathogenesis of VVC. Therefore, preventing the adhesion of C. albicans to vaginal epithelial cells may be one of the most effective strategies for the treatment of VVC. Berberine (BBR) is a biologically active herbal alkaloid that was used to treat VVC. However, so far, its mechanism has remained unclear. This study shows BBR significantly inhibits the adhesion of C. albicans to vaginal epithelial cells by reducing the expressions of ICAM-1, mucin1, and mucin4 in vaginal epithelial cells, which play the most important role in modulating the adhesion of C. albicans to host cells, and balancing IL-2 and IL-4 expressions, which play a key effect on regulating the inflammatory response caused by C. albicans infection. Hence, our findings demonstrate that BBR may be a potential therapeutic agent for VVC by interfering with the adhesion of C. albicans to vaginal epithelial cells and represents a new pathway for developing antifungal therapies agents from natural herbs.
Phytochemistry in the Ethnopharmacology of North and Central America
Authors: Arnason John Thor , Harris Cory S. , Guerrero-Analco José A.
Published: February 2022

Traditionally the role of phytochemistry in the ethnopharmacology of North and Central America has been to characterize plant materials so that they can be produced reproducibly for commercial use or to identify active principles in unstudied traditional medicines for drug discovery. With new decolonial objectives coming from Indigenous communities, emphasis has shifted to evaluating the safety and efficacy of traditional medicines and preparations for community use. With new techniques and technologies available, scientific focus has shifted from individual bioactives to more rapid and comprehensive chemical characterizations and polypharmacy of traditional medicines. Untargeted metabolomics and associated statistical treatments have greatly expanded identification of components, improved species and cultivar identification and provided means for identifying multiple activity biomarkers, via chemometric and biochemometric analysis. New integrated techniques are available for identifying multiple active principles and synergists. The recent explosion of information is not without problems that need to be addressed including many unconfirmed tentative identifications of phytochemicals, lack of quantitative testing, superficial chemical activity testing and continuing need for dereplication.
Emerging Roles of Sodium Glucose Cotransporter 2 (SGLT-2) Inhibitors in Diabetic Cardiovascular Diseases: Focusing on Immunity, Inflammation and Metabolism
Authors: Xie Lingxiang , Xiao Yang , Tai Shi , Yang Huijie , Zhou Shenghua , Zhou Zhiguang
Published: February 2022

Diabetes mellitus (DM) is one of the most fast evolving global issues characterized by hyperglycemia. Patients with diabetes are considered to face with higher risks of adverse cardiovascular events. Those are the main cause of mortality and disability in diabetes patients. There are novel antidiabetic agents that selectively suppress sodium-glucose cotransporter-2 (SGLT-2). They work by reducing proximal tubule glucose reabsorption. Although increasing evidence has shown that SGLT-2 inhibitors can contribute to a series of cardiovascular benefits in diabetic patients, including a reduced incidence of major adverse cardiovascular events and protection of extracardiac organs, the potential mechanisms of SGLT2 inhibitors’ cardiovascular protective effects are still not fully elucidated. Given the important role of inflammation and metabolism in diabetic cardiovascular diseases, this review is intended to rationally compile the multifactorial mechanisms of SGLT-2 inhibitors from the point of immunity, inflammation and metabolism, depicting the fundamental cellular and molecular processing of SGLT-2 inhibitors exerting regulating immunity, inflammation and metabolism. Finally, future directions and perspectives to prevent or delay cardiovascular complications in DM by SGLT-2 inhibitors are presented.