bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Characteristics and Genetic Analysis of a Family With Birt-Hogg-Dubé Syndrome and Congenital Contractural Arachnodactyly
Authors: Qiu Jiayong , Lou Yao , Zhu Yingwei , Wang Min , Peng Huifang , Hao Yingying , Jiang Hongwei , Mao Yimin
Published: January 2022

Background: Birt-Hogg-Dubé (BHD) syndrome and congenital contractural arachnodactyly (CCA) or Beals-Hecht syndrome are clinically rare autosomal dominant genetic diseases. In this study, we describe an extremely rare family with BHD syndrome and CCA.

Objective: To investigate the clinical and genetic characteristics of a family with BHD syndrome and CCA.

Methods: We describe the clinical characteristics, family history, and clinical manifestations of the patient’s family members. The patient underwent a blood test, computed tomography (CT) of the chest, color Doppler ultrasound of the abdomen and heart, and digital radiography of the hands. Whole exome sequencing was performed on his family members.

Results: Two years ago, the male proband developed chest tightness and shortness of breath that was accompanied by an irritating cough as well as repeated (four times) spontaneous pneumothorax. The chest CT indicated spontaneous pneumothorax on the right side and cyst and bullae in both lungs. He had no kidney tumors or skin lesions. His son had a history of pulmonary bullae and experienced spontaneous pneumothorax twice. The proband, his mother, and his son were all born with a hand deformity. The sequencing results demonstrated that both the proband and his son had heterozygous variations of the folliculin (FLCN) gene c.1015C > T (p. Gln339Ter) and fibrillin-2 (FBN2) gene c.3485G > A (p. Cys1162Tyr), which are associated with BHD syndrome and CCA, respectively.

Conclusion: For patients with chest tightness, shortness of breath, recurrent spontaneous pneumothorax, and congenital hand deformity without inducement, genetic testing should be carried out as soon as possible to make a clear diagnosis, which can then guide treatment and genetic counseling.
Computational System Level Approaches for Discerning Reciprocal Regulation of IL10 and IL12 in Leishmaniasis
Authors: Khandibharad Shweta , Singh Shailza
Published: January 2022

IL12 and IL10 are two of the major cytokines which control the fate of Leishmaniasis. This paper presents two models healthy state and diseased state which shows how secretion of IL12 is responsible for parasite elimination and IL10 can jeopardize the parasite elimination and promote its survival. Epigenetic modification in the host IL12 and IL10 promoter can decide the fate of parasites. It was observed that reciprocal relationship exists between IL12 and IL10 and that is majorly controlled by a transcription factor NFAT5 from Rel family of transcription factors. By targeting this transcription factor at the cellular level, it might be possible to modulate the release of powerful pro-inflammatory cytokines, thereby reducing parasite survival. The mathematical models developed here serves as a step towards finding a key component that can pave a way for therapeutic investigation.
A Compound Heterozygous Mutation in Calpain 1 Identifies a New Genetic Cause for Spinal Muscular Atrophy Type 4 (SMA4)
Authors: Perez-Siles G. , Ellis M. , Ashe A. , Grosz B. , Vucic S. , Kiernan M. C. , Morris K. A. , Reddel S. W. , Kennerson M. L.
Published: January 2022

Spinal Muscular Atrophy (SMA) is a heterogeneous group of neuromuscular diseases characterized by degeneration of anterior horn cells of the spinal cord, leading to muscular atrophy and weakness. Although the major cause of SMA is autosomal recessive exon deletions or loss-of-function mutations of survival motor neuron 1 (SMN1) gene, next generation sequencing technologies are increasing the genetic heterogeneity of SMA. SMA type 4 (SMA4) is an adult onset, less severe form of SMA for which genetic and pathogenic causes remain elusive.Whole exome sequencing in a 30-year-old brother and sister with SMA4 identified a compound heterozygous mutation (p. G492R/p. F610C) in calpain-1 (CAPN1). Mutations in CAPN1 have been previously associated with cerebellar ataxia and hereditary spastic paraplegia. Using skin fibroblasts from a patient bearing the p. G492R/p. F610C mutation, we demonstrate reduced levels of CAPN1 protein and protease activity. Functional characterization of the SMA4 fibroblasts revealed no changes in SMN protein levels and subcellular distribution. Additional cellular pathways associated with SMA remain unaffected in the patient fibroblasts, highlighting the tissue specificity of CAPN1 dysfunction in SMA4 pathophysiology. This study provides genetic and functional evidence of CAPN1 as a novel gene for the SMA4 phenotype and expands the phenotype of CAPN1 mutation disorders.
Human Oral Epithelial Cells Suppress T Cell Function via Prostaglandin E2 Secretion
Authors: Sanchez-Trincado Jose L. , Pelaez-Prestel Hector F. , Lafuente Esther M. , Reche Pedro A.
Published: January 2022

The oral mucosa is constantly exposed to a plethora of stimuli including food antigens, commensal microbiota and pathogens, requiring distinct immune responses. We previously reported that human oral epithelial cells (OECs) suppress immune responses to bacteria, using H413 and TR146 OEC lines and primary OECs in co-culture with dendritic cells (DCs) and T cells (OEC-conditioned cells). OECs reduced DCs expression of CD80/CD86 and IL-12/TNFα release and impaired T cell activation. Here, we further evaluated the immunosuppression by these OECs and investigated the underlying mechanisms. OEC-conditioned DCs did not induce CD4 T cell polarization towards Treg, judging by the absence of FoxP3 expression. OECs also repressed T-bet/IFNγ expression in CD4 and CD8 T cells activated by DCs or anti-CD3/CD28 antibodies. This inhibition depended on OEC:T cell ratio and IFNγ repression occurred at the transcriptional level. Time-lapse experiments showed that OECs inhibited early steps of T cell activation, consistent with OECs inability to suppress T cells stimulated with PMA/ionomycin. Blocking CD40/CD40L, CD58/CD2 and PD-L1/PD-1 interactions with specific antibodies did not disrupt T cell suppression by OECs. However, preventing prostaglandin E2 (PGE2) synthesis or blocking PGE2 binding to the cognate EP2/EP4 receptors, restored IFNγ and TNFα production in OEC-conditioned T cells. Finally, treating OECs with poly(I:C), which simulates viral infections, limited T cell suppression. Overall, these results point to an inherent ability of OECs to suppress immune responses, which can nonetheless be eluded when OECs are under direct assault.
Long-Term Suppression of Circulating Proinflammatory Cytokines in Multiple Sclerosis Patients Following Autologous Haematopoietic Stem Cell Transplantation
Authors: Hendrawan Kevin , Khoo Melissa L. M. , Visweswaran Malini , Massey Jennifer C. , Withers Barbara , Sutton Ian , Ma David D. F. , Moore John J.
Published: January 2022

Autologous haematopoietic stem cell transplantation (AHSCT) is a therapeutic option for haematological malignancies, such as non-Hodgkin’s lymphoma (NHL), and more recently, for autoimmune diseases, such as treatment-refractory multiple sclerosis (MS). The immunological mechanisms underlying remission in MS patients following AHSCT likely involve an anti-inflammatory shift in the milieu of circulating cytokines. We hypothesised that immunological tolerance in MS patients post-AHSCT is reflected by an increase in anti-inflammatory cytokines and a suppression of proinflammatory cytokines in the patient blood. We investigated this hypothesis using a multiplex-ELISA assay to compare the concentrations of secreted cytokine in the peripheral blood of MS patients and NHL patients undergoing AHSCT. In MS patients, we detected significant reductions in proinflammatory T helper (Th)17 cytokines interleukin (IL)-17, IL-23, IL-1β, and IL-21, and Th1 cytokines interferon (IFN)γ and IL-12p70 in MS patients from day 8 to 24 months post-AHSCT. These changes were not observed in the NHL patients despite similar pre-conditioning treatment for AHSCT. Some proinflammatory cytokines show similar trends in both cohorts, such as IL-8 and tumour necrosis factor (TNF)-α, indicating a probable treatment-related AHSCT response. Anti-inflammatory cytokines (IL-10, IL-4, and IL-2) were only transiently reduced post-AHSCT, with only IL-10 exhibiting a significant surge at day 14 post-AHSCT. MS patients that relapsed post-AHSCT exhibited significantly elevated levels of IL-17 at 12 months post-AHSCT, unlike non-relapse patients which displayed sustained suppression of Th17 cytokines at all post-AHSCT timepoints up to 24 months. These findings suggest that suppression of Th17 cytokines is essential for the induction of long-term remission in MS patients following AHSCT.
Single-Cell RNA Sequencing in Lung Cancer: Revealing Phenotype Shaping of Stromal Cells in the Microenvironment
Authors: Zhang Jianhong , Song Chengyang , Tian Ye , Yang Xueying
Published: January 2022

The lung tumor microenvironment, which is composed of heterogeneous cell populations, plays an important role in the progression of lung cancer and is closely related to therapeutic efficacy. Increasing evidence has shown that stromal components play a key role in regulating tumor invasion, metastasis and drug resistance. Therefore, a better understanding of stromal components in the tumor microenvironment is helpful for the diagnosis and treatment of lung cancer. Rapid advances in technology have brought our understanding of disease into the genetic era, and single-cell RNA sequencing has enabled us to describe gene expression profiles with unprecedented resolution, enabling quantitative analysis of gene expression at the single-cell level to reveal the correlations among heterogeneity, signaling pathways, drug resistance and microenvironment molding in lung cancer, which is important for the treatment of this disease. In this paper, several common single-cell RNA sequencing methods and their advantages and disadvantages are briefly introduced to provide a reference for selection of suitable methods. Furthermore, we review the latest progress of single-cell RNA sequencing in the study of stromal cells in the lung tumor microenvironment.
Effect of D-Ala-Ended Peptidoglycan Precursors on the Immune Regulation of Lactobacillus plantarum Strains
Authors: Song Xin , Li Fengjiao , Zhang Mingshu , Xia Yongjun , Ai Lianzhong , Wang Guangqiang
Published: January 2022

The resistance of Lactobacillus plantarum to vancomycin depends on its peptidoglycan composition. Vancomycin has poor binding affinity with peptidoglycan precursors ending in D-alanyl-D-lactate (D-Ala-D-Lac) but binds strongly to peptidoglycan precursors ending in D-alanyl-D-alanine (D-Ala-D-Ala), resulting in resistance and sensitivity, respectively. The ligase Ddl, which generates D-Ala-D-Lac or D-Ala-D-Ala incorporated into the peptidoglycan precursor chain, is responsible for this specificity. To study the effect of peptidoglycan precursors on immunity, we constructed several strains of L. plantarum expressing the ddl gene of Lactococcus lactis to change their peptidoglycan precursors. The change in the termini of the peptidoglycan precursors was determined by the sensitivity of the strains to vancomycin. The overexpression of ddl increased the susceptibility of the strains to vancomycin. We further explored the regulation of the macrophage inflammatory response pathway by the wild-type and constructed strains, and found that these strains induced the MyD88-dependent TRAF6/MAPK pathway, and the increase in D-Ala L. plantarum peptidoglycan precursors increased the secretion of the inflammatory factors IL-6, IL-1β and TNF-α. These results indicate that D-Ala-ended peptidoglycan precursors play a central role in the variable immunomodulatory ability of L. plantarum.
Kinetics of the Antibody Response to Boostering With Three Different Vaccines Against SARS-CoV-2
Authors: Markewitz Robert , Juhl David , Pauli Daniela , Görg Siegfried , Junker Ralf , Rupp Jan , Engel Sarah , Steinhagen Katja , Herbst Victor , Zapf Dorinja , Krüger Christina , Brockmann Christian , Leypoldt Frank , Dargvainiene Justina , Schomburg Benjamin , Sharifzadeh Shahpour , Nejad Lukas Salek , Wandinger Klaus-Peter , Ziemann Malte
Published: January 2022

Background

Heterologous vaccinations against SARS-CoV-2 with ChAdOx1 nCoV-19 and a second dose of an mRNA-based vaccine have been shown to be more immunogenic than homologous ChAdOx1 nCoV-19. In the current study, we examined the kinetics of the antibody response to the second dose of three different vaccination regimens (homologous ChAdOx1 nCoV-19 vs. ChAdOx1 nCoV-19 + BNT162b2 or mRNA-1273) against SARS-CoV-2 in a longitudinal manner; whether there are differences in latency or amplitude of the early response and which markers are most suitable to detect these responses.

Methods

We performed assays for anti-S1 IgG and IgA, anti-NCP IgG and a surrogate neutralization assay on serum samples collected from 57 participants on the day of the second vaccination as well as the following seven days.

Results

All examined vaccination regimens induced detectable antibody responses within the examined time frame. Both heterologous regimens induced responses earlier and with a higher amplitude than homologous ChAdOx1 nCoV-19. Between the heterologous regimens, amplitudes were somewhat higher for ChAdOx1 nCoV-19 + mRNA-1273. There was no difference in latency between the IgG and IgA responses. Increases in the surrogate neutralization assay were the first changes to be detectable for all regimens and the only significant change seen for homologous ChAdOx1 nCoV-19.

Discussion

Both examined heterologous vaccination regimens are superior in immunogenicity, including the latency of the response, to homologous ChAdOx1 nCoV-19. While the IgA response has a shorter latency than the IgG response after the first dose, no such difference was found after the second dose, implying that both responses are driven by separate plasma cell populations. Early and steep increases in surrogate neutralization levels suggest that this might be a more sensitive marker for antibody responses after vaccination against SARS-CoV-2 than absolute levels of anti-S1 IgG.
Near-Infrared Activation of Sensory Rhodopsin II Mediated by NIR-to-Blue Upconversion Nanoparticles
Authors: Yaguchi Momo , Jia Xiaodan , Schlesinger Ramona , Jiang Xiue , Ataka Kenichi , Heberle Joachim
Published: January 2022

Direct optical activation of microbial rhodopsins in deep biological tissue suffers from ineffective light delivery because visible light is strongly scattered and absorbed. NIR light has deeper tissue penetration, but NIR-activation requires a transducer that converts NIR light into visible light in proximity to proteins of interest. Lanthanide-doped upconversion nanoparticles (UCNPs) are ideal transducer as they absorb near-infrared (NIR) light and emit visible light. Therefore, UCNP-assisted excitation of microbial rhodopsins with NIR light has been intensively studied by electrophysiology technique. While electrophysiology is a powerful method to test the functional performance of microbial rhodopsins, conformational changes associated with the NIR light illumination in the presence of UCNPs remain poorly understood. Since UCNPs have generally multiple emission peaks at different wavelengths, it is important to reveal if UCNP-generated visible light induces similar structural changes of microbial rhodopsins as conventional visible light illumination does. Here, we synthesize the lanthanide-doped UCNPs that convert NIR light to blue light. Using these NIR-to-blue UCNPs, we monitor the NIR-triggered conformational changes in sensory rhodopsin II from Natronomonas pharaonis (NpSRII), blue light-sensitive microbial rhodospsin, by FTIR spectroscopy. FTIR difference spectrum of NpSRII was recorded under two different excitation conditions: (ⅰ) with conventional blue light, (ⅱ) with UCNP-generated blue light upon NIR excitation. Both spectra display similar spectral features characteristic of the long-lived M photointermediate state during the photocycle of NpSRII. This study demonstrates that NIR-activation of NpSRII mediated by UCNPs takes place in a similar way to direct blue light activation of NpSRII.
New Age Detection of Viruses: The Nano-Biosensors
Authors: Shand Harshita , Dutta Swarnab , Rajakumar Santhosh , James Paulraj Shalini , Mandal Amit Kumar , KT Ramya Devi , Ghorai Suvankar
Published: January 2022

Viruses and their related diseases have always posed a significant hazard to humans. The current pandemic caused by the Covid-19 (SARS-CoV-2) virus is the latest illustration of what this tiny organism can do to humanity at large, putting everything on the brink of collapse. So it is reasonable that early diagnosis of infection from viruses remains a crucial step to prevent such human suffering. Many traditional methods are already in use for detecting viruses, including molecular approaches, serological methods, direct virus culture methods, and so on. Such traditional methods though are brilliant at some stages but are not devoid of drawbacks. To overcome the limits of conventional procedures, new techniques have been developed which tried to eradicate the demerits of the former procedures. Biosensors have come up with a lot of promises in terms of detecting viruses and diseases connected with them. The development of various types of such biosensors such as Affinity-based nano-biosensors, Nanoisland affinity-based biosensors, Graphene affinity-based biosensors, Nanowires based biosensors, Optical nano biosensors, Fiber optic nano-biosensors, Surface Plasmon Resonance (SPR) based optical nano-biosensors, Total internal reflection fluorescence, Surface-Enhanced Raman Scattering (SERS), Electrochemical nano-biosensors had helped us in the rapid and sensitive detection of viruses. Aid to these nanosensors, viral detection now becomes very sensitive, rapid and cost has come down to a significant low. In this review, an attempt has been made to compile all of the different nano-biosensors and their applications. Due attention is given to the fact that the reader gets the grasp of the concept with much ease.
Adherence to the Mediterranean Diet and Its Association With Sleep Quality and Chronotype Among Youth: A Cross-Sectional Study
Authors: Naja Farah , Hasan Hayder , Khadem Safiya Hassan , Buanq Maryam Ahmed , Al-Mulla Haya Khalid , Aljassmi Aysha Khalifa , Faris MoezAlIslam Ezzat
Published: January 2022

Background

Evidence indicates that many university students have poor adherence to a healthy diet accompanied by unhealthy lifestyle behaviors. Chrono-nutrition is an emerging field of research that examines the pattern of optimum daily activity in relation to the human's dietary patterns, and their reflections of variable health indicators such as sleep quality. However, there is a scarcity of research that examines the relationship between adherence to the healthy eating pattern, like the Mediterranean diet (MD), with sleep quality and chronotype among university students.

Methods

A cross-sectional study was conducted, and convenience sampling was used. Participants were assessed for adherence to the MD using the Mediterranean Diet Quality Index (KIDMED), for sleep quality using the Pittsburgh Sleep Quality Index (PSQI), and for chronotype using the Morningness-Eveningness questionnaire (MEQ).

Results

The study included 503 university students, most of them (81.5%) were females. Only 15.1 and 16.9% reported morningness chronotype and good sleep quality, respectively. About half of the students showed medium and high adherence to the KIMED. In-depth analysis revealed that students with good adherence to the MD were more likely to have a good sleep quality (OR = 0.35; 95%CI: 0.21–0.59; P < 0.001) even after adjustment for age and sex (OR = 0.36; 95%CI: 0.21–0.62; P < 0.001). The regression analysis also showed that those with good adherence to the MD had a significant association with better subjective sleep quality, less sleep latency, sleep disturbance, and daytime dysfunction even after adjustment for age and sex. Those with morningness chronotype had about a six-fold higher chance to have good adherence to the MD (OR = 5.67; 95%CI: 2.86–11.26; P < 0.001, respectively).

Conclusions

Good adherence to the healthy diet presented in the MD among university students is associated with morningness chronotype and with improved overall sleep quality and sleep components. Long-term, controlled intervention research works are warranted for more elaboration on the impact of chronotype and dietary habits on sleep quality and other important aspects such as mental health and academic achievement.
Establishing a Predictive Nomogram for Cervical Lymph Node Metastasis in Patients With Papillary Thyroid Carcinoma
Authors: Hu Qiao , Zhang Wang-Jian , Liang Li , Li Ling-Ling , Yin Wu , Su Quan-Li , Lin Fei-Fei
Published: January 2022

Objectives

The purpose of this study was to establish a nomogram for predicting cervical lymph node metastasis (CLNM) in patients with papillary thyroid carcinoma (PTC).

Materials and Methods

A total of 418 patients with papillary thyroid carcinoma undergoing total thyroidectomy with cervical lymph node dissection were enrolled in the retrospective study from January 2016 to September 2019. Univariate and multivariate Logistic regression analysis were performed to screen the clinicopathologic, laboratory and ultrasound (US) parameters influencing cervical lymph nodes metastasis and develop the predicting model.

Results

CLNM was proved in 34.4% (144/418) of patients. In the multivariate regression analysis, Male, Age < 45 years, Tumor size > 20mm, multifocality, ambiguous boundary, extracapsular invasion and US-suggested lymph nodes metastasis were independent risk factors of CLNM (p < 0.05). Prediction nomogram showed an excellent discriminative ability, with a C-index of 0.940 (95% confidence interval [CI], 0.888-0.991), and a good calibration.

Conclusion

The established nomogram showed a good prediction of CLNM in patients with PTC. It is conveniently used and should be considered in the determination of surgical procedures.
Primary Thyroid NUT Carcinoma With High PD-L1 Expression and Novel Massive IGKV Gene Fusions: A Case Report With Treatment Implications and Literature Review
Authors: Zhou Juan , Duan Miao , Jiao Qiong , Chen Chunyan , Xing Aiyan , Su Peng , Tang Juan , Zhang Hui , Liu Zhiyan
Published: January 2022

Background

Nuclear protein in testis (NUT) carcinoma (NC) is a rare and aggressive undifferentiated carcinoma that typically arises from midline supradiaphragmatic structures. It is uniquely driven by a NUT gene rearrangement on chromosome 15q14. Few thyroid NCs have been reported and there are no established treatment guidelines for NUT carcinoma.

Method

Ultrasound-guided fine needle aspiration smear was performed for the preoperative diagnosis of thyroid lesions. Cytopathology, histology, and immunochemical staining all indicated NC. Fluorescence in situ hybridization (FISH), qRT-PCR, and next-generation sequencing (NGS) were used to analyze the genetic characteristics of NC.

Results

We describe a rare case of thyrogenic NC in a 38-year-old male with cytological, histological, immunohistochemical, and genetic features. Cytological smears and histopathological specimens showed typical features of NC. Immunohistochemistry confirmed strong immunoreactivity with NUT, EMA, P63, TTF-1, and c-myc. CK19 was positive exclusively in sudden keratosis. No immunoreactivity was found for neuroendocrine markers. FISH was applied to isolate the NUT gene on chromosome 15q14. The NGS results revealed a BRD4-NUT gene fusion, which was further confirmed by RT-qPCR. Structural variation (SV) of NUTM1 occurred in the exon region, and the mutation site was 15q14. Moreover, BRD4 single-nucleotide variation (SNV) occurs in the 3′ UTR at mutation site 19p13.12. The PD-L1 combined predictive score was over 30%. The patient received chemotherapy, followed by programmed cell death 1 (PD-1) inhibition with camrelizumab, and died 10 months after surgery.

Conclusion

Thyroid NC is an extremely rare and fatal malignant tumor. It is necessary to consider NC when squamous differentiation is observed cytologically or histologically. NGS is an effective tool for obtaining the final diagnosis and obtaining a better understanding of tumor pathogenesis. A large number of IGKV gene fusions in addition to the BRD4-NUT fusion may play a role in the pathogenesis and immunotherapy response of NC. Immunotherapy for NC remains to be explored due to the rarity of this aggressive malignancy.
Predictive Effect of Systemic Immune-Inflammation Index Combined With Prognostic Nutrition Index Score on Efficacy and Prognosis of Neoadjuvant Intraperitoneal and Systemic Paclitaxel Combined With Apatinib Conversion Therapy in Gastric Cancer Patients With Positive Peritoneal Lavage Cytology: A Prospective Study
Authors: Ding Ping’an , Yang Peigang , Sun Chenyu , Tian Yuan , Guo Honghai , Liu Yang , Li Yong , Zhao Qun
Published: January 2022

Background

Gastric cancer with only peritoneal lavage cytology (GC-CY1) is a special type of gastric cancer, which is defined as stage IV. The pre-treatment systemic immune-inflammation index (SII) and prognostic nutritional index (PNI) are representative blood indexes of systemic inflammatory response and nutritional status. However, the clinical significance of combined detection of these two indexes is still unclear. This study aims to evaluate the clinical value of the new score system by combining SII and PNI (SII-PNI score) as a predictor of efficacy and prognosis after neoadjuvant intraperitoneal and systemic (NIPS) paclitaxel combined with Apatinib conversion therapy for GC-CY1 patients.

Methods

We registered a prospective clinical study involving 36 GC-CY1 patients from April 2018 to August 2019 (NCT03718624). All patients underwent re-laparoscopic exploration after treatment. According to free cancer cells (FCCs) status, these patients were divided into FCCs group and non-FCCs group. The SII-PNI score ranged from 0 to 2 as follows: score of 2, high SII (≥512.1) and low PNI (≤52.9); score of 1, either high SII or low PNI; score of 0, no high SII nor low PNI.

Results

All patients underwent re-laparoscopic exploration after 3 cycles of NIPS paclitaxel and Apatinib conversion therapy. Among them, 28 cases (77.78%) were in non-FCCs group, and 8 cases (22.22%) were in FCCs group. The SII-PNI score of non-FCCs patients was significantly lower than that of FCCs patients (p=0.041). The prognosis of patients with high SII-PNI score was significantly worse than that of patients with low SII-PNI score (p<0.001). Multivariate analysis showed that SII-PNI score was an independent prognostic factor for predicting overall survival and progression-free survival (p=0.001, 0.002).

Conclusion

Pretreatment SII-PNI score is an important predictor for the efficacy of GC-CY1 patients after NIPS paclitaxel combined with Apatinib conversion therapy, which can help to identify high-risk groups and predict prognosis.
Treatment Interruptions During Stereotactic Body Radiotherapy for Prostate Cancer
Authors: Pepin Abigail N. , Zwart Alan , Danner Malika , Ayoob Marylin , Yung Thomas , Collins Brian T. , Kumar Deepak , Suy Simeng , Aghdam Nima , Collins Sean P.
Published: January 2022

Background

During the course of radiation treatment for prostate cancer, patients may have unintentional interruptions in their treatment course due to a wide variety of factors. Stereotactic body radiation therapy (SBRT) decreases the number of treatments compared to conventionally fractionated radiation; hence, it has the potential to decrease treatment delays and non-completion. This study sought to determine the incidence of treatment delay and characterize the etiology and length in a large cohort of men treated with SBRT for their prostate cancer.

Methods

One thousand three hundred and thirty-six patients treated with SBRT from 2008 to 2021 at the Georgetown University Hospital for prostate cancer were included in this retrospective study. A treatment delay was defined as a patient requiring longer than 14 days to complete 5 fractions of SBRT. Non-completion was defined as patients treated with less than 5 fractions. In the patients who experienced delays, chart review was performed to characterize the length and etiology of each delay. Multivariate analysis was performed via binary logistic regression modeling on PSPP.

Results

All individuals in the cohort eventually completed the planned 5-fraction regimen. Thirty-three patients experienced a treatment delay. Median length of time to complete treatment was 11 days (range 5–155 days). In patients who experienced a delay, nearly half (45.5%) experienced only a one-day delay. The most common reason for a delay was a technical issue (48.5%), including the machine maintenance, fiducial misalignment, or inadequate pretreatment bowel preparation. Other reasons included unplanned breaks due to acute side effects (21.2%), logistical issues (18.2%), non-treatment related health issues (9.1%), and inclement weather (3.0%). There were no significant sociodemographic, oncologic, or treatment variables that predicted treatment interruption on multivariate analysis.

Conclusions

The incidence of treatment interruptions in patients undergoing SBRT for their prostate cancer was low. Most treatment delays were short.
A Frog Peptide Ameliorates Skin Photoaging Through Scavenging Reactive Oxygen Species
Authors: Feng Guizhu , Wei Lin , Che Helong , Shen Yan , Yang Jun , Mi Kai , Liu Jin , Wu Jing , Yang Hailong , Mu Lixian
Published: January 2022

Although many bioactive peptides have been identified from the frog skins, their protective effects and the molecular mechanisms against skin photodamage are still poorly understood. In this study, a novel 20-residue peptide (antioxidin-NV, GWANTLKNVAGGLCKMTGAA) was characterized from the skin of plateau frogNanorana ventripunctata. Antioxidin-NV obviously decreased skin erythema, thickness and wrinkle formation induced by Ultraviolet (UV) B exposure in hairless mice. In UVB-irradiated keratinocytes (HaCaT cells) and hairless mice, it effectively inhibited DNA damage through reducing p-Histone H2A.X (γH2AX) expression, alleviated cell apoptosis by decreasing the expression of apoptosis-specific protein (cleaved caspase 3), and reduced interleukin-6 (IL-6) productionviablocking UVB-activated Toll-like receptor 4 (TLR4)/p38/JNK/NF-κB signaling. In UVB-irradiated human skin fibroblasts (HSF cells) and hairless mice, it effectively restored HSF cells survival rate, and rescued α-SMA accumulation and collagen (especially type I collagen) production by restoring transforming growth factor-β1 (TGF-β1)/Smad2 signaling. We found that antioxidin-NV directly and rapidly scavenged intracellular and mitochondrial ROS in HaCaT cells upon UVB irradiation, and quickly eliminated the artificial free radicals, 2, 2′-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+). Taken together, antioxidin-NV directly and rapidly scavenged excessive ROS upon UVB irradiation, subsequently alleviated UVB-induced DNA damage, cell apoptosis, and inflammatory response, thus protecting against UVB-induced skin photoaging. These properties makes antioxidin-NV an excellent candidate for the development of novel anti-photoaging agent.
FGFC1 Selectively Inhibits Erlotinib-Resistant Non-Small Cell Lung Cancer via Elevation of ROS Mediated by the EGFR/PI3K/Akt/mTOR Pathway
Authors: Yan Shike , Zhang Bing , Feng Jingwen , Wu Haigang , Duan Namin , Zhu Yamin , Zhao Yueliang , Shen Shuang , Zhang Kai , Wu Wenhui , Liu Ning
Published: January 2022

Non-small cell lung cancer (NSCLC) is one of the most common malignancies in the world. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been used as a first-line treatment for patients harboring with EGFR mutations in advanced NSCLC. Nevertheless, the drug resistance after continuous and long-term chemotherapies considerably limits its clinical efficacy. Therefore, it is of great importance to develop new chemotherapeutic agents and treatment strategies to conquer the drug resistance. FGFC1 (Fungi fibrinolytic compound 1), a type of bisindole alkaloid from a metabolite of the rare marine fungi Starchbotrys longispora. FG216, has exhibited excellent fibrinolytic and anti-inflammatory activity. However, the potent efficacy of FGFC1 in human cancer therapy requires further study. Herein, we demonstrated that FGFC1 selectively suppressed the growth of NSCLC cells with EGFR mutation. Mechanistically, FGFC1 treatment significantly induced the apoptosis of erlotinib-resistant NSCLC cells H1975 in a dose-dependent manner, which was proved to be mediated by mitochondrial dysfunction and elevated accumulation of intracellular reactive oxygen species (ROS). Scavenging ROS not only alleviated FGFC1-induced apoptosis but also relieved the decrease of phospho-Akt. We further confirmed that FGFC1 significantly decreased the phosphorylation of protein EGFR, phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), and mammalian target of rapamycin (mTOR) in H1975 cells. Notably, PI3K inhibitor (LY294002) could promote the accumulation of ROS and the expression levels of apoptosis-related proteins induced by FGFC1. Molecular dynamics simulations indicated that FGFC1 can inhibit EGFR and its downstream PI3K/Akt/mTOR pathway through directly binding to EGFR, which displayed a much higher binding affinity to EGFRT790M/L858R than EGFRWT. Additionally, FGFC1 treatment also inhibited the migration and invasion of H1975 cells. Finally, FGFC1 effectively inhibited tumor growth in the nude mice xenograft model of NSCLC. Taken together, our results indicate that FGFC1 may be a potential candidate for erlotinib-resistant NSCLC therapy.
Hermansky-Pudlak Syndrome: Identification of Novel Variants in the Genes HPS3, HPS5, and DTNBP1 (HPS-7)
Authors: Boeckelmann Doris , Wolter Mira , Neubauer Katharina , Sobotta Felix , Lenz Antonia , Glonnegger Hannah , Käsmann-Kellner Barbara , Mann Jasmin , Ehl Stephan , Zieger Barbara
Published: January 2022

Hermansky-Pudlak syndrome (HPS), a rare heterogeneous autosomal recessive disorder, is characterized by oculocutaneous albinism (OCA) and a bleeding diathesis due to a defect regarding melanosomes and platelet delta (δ)-granule secretion. Interestingly, patients with HPS type 2 (HPS-2) or HPS type 10 (HPS-10) present additionally with an immunological defect. We investigated three patients (IP1, IP2, and IP3) who suffer from a bleeding diathesis. Platelet aggregometry showed impaired platelet function and flow cytometry revealed a severely reduced platelet CD63 expression hinting to either a defect of platelet delta granule secretion or a decreased number of delta granules in these patients. However, only IP3 presents with an apparent OCA. We performed panel sequencing and identified a homozygous deletion of exon 6 in DTNBP1 for IP3. Western analysis confirmed the absence of the encoded protein dysbindin confirming the diagnosis of HPS-7. Interestingly, this patient reported additionally recurrent bacterial infections. Analysis of lymphocyte cytotoxicity showed a slightly reduced NK-degranulation previously documented in a more severe form in patients with HPS-2 or HPS-10. IP1 is carrier of two compound heterozygous variants in the HPS3 gene (c.65C > G and c.1193G > A). A homozygous variant in HPS5 (c.760G > T) was identified in IP2. The novel missense variants were classified as VUS (variant of uncertain significance) according to ACMG guidelines. For IP1 with the compound heterozygous variants in HPS3 a specialized ophthalmological examination showed ocular albinism. HPS3 and HPS5 encode subunits of the BLOC-2 complex and patients with HPS-3 or HPS-5 are known to present with variable/mild hypopigmentation.
Physiologically Based Pharmacokinetic Modeling in Pregnant Women Suggests Minor Decrease in Maternal Exposure to Olanzapine
Authors: Zheng Liang , Yang Hongyi , Dallmann André , Jiang Xuehua , Wang Ling , Hu Wei
Published: January 2022

Pregnancy is accompanied by significant physiological changes that might affect the in vivo drug disposition. Olanzapine is prescribed to pregnant women with schizophrenia, while its pharmacokinetics during pregnancy remains unclear. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model of olanzapine in the pregnant population. With the contributions of each clearance pathway determined beforehand, a full PBPK model was developed and validated in the non-pregnant population. This model was then extrapolated to predict steady-state pharmacokinetics in the three trimesters of pregnancy by introducing gestation-related alterations. The model adequately simulated the reported time-concentration curves. The geometric mean fold error of Cmax and AUC was 1.14 and 1.09, respectively. The model predicted that under 10 mg daily dose, the systematic exposure of olanzapine had minor changes (less than 28%) throughout pregnancy. We proposed that the reduction in cytochrome P4501A2 activity is counteracted by the induction of other enzymes, especially glucuronyltransferase1A4. In conclusion, the PBPK model simulations suggest that, at least at the tested stages of pregnancy, dose adjustment of olanzapine can hardly be recommended for pregnant women if effective treatment was achieved before the onset of pregnancy and if fetal toxicity can be ruled out.
Biologics in Asthma: A Molecular Perspective to Precision Medicine
Authors: Salter Brittany , Lacy Paige , Mukherjee Manali
Published: January 2022

Recent developments in therapeutic strategies have provided alternatives to corticosteroids as the cornerstone treatment for managing airway inflammation in asthma. The past two decades have witnessed a tremendous boost in the development of anti-cytokine monoclonal antibody (mAb) therapies for the management of severe asthma. Novel biologics that target eosinophilic inflammation (or type 2, T2 inflammation) have been the most successful at treating asthma symptoms, though there are a few in the drug development pipeline for treating non-eosinophilic or T2-low asthma. There has been significant improvement in clinical outcomes for asthmatics treated with currently available monoclonal antibodies (mAbs), including anti-immunoglobulin (Ig) E, anti-interleukin (IL)-4 receptor α subunit, anti-IL-5, anti-IL-5Rα, anti-IL-6, anti-IL-33, and anti-thymic stromal lymphopoietin (TSLP). Despite these initiatives in precision medicine for asthma therapy, a significant disease burden remains, as evident from modest reduction of exacerbation rates, i.e., approximately 40–60%. There are numerous studies that highlight predictors of good responses to these biologics, but few have focused on those who fail to respond adequately despite targeted treatment. Phenotyping asthmatics based on blood eosinophils is proving to be inadequate for choosing the right drug for the right patient. It is therefore pertinent to understand the underlying immunology, and perhaps, carry out immune endotyping of patients before prescribing appropriate drugs. This review summarizes the immunology of asthma, the cytokines or receptors currently targeted, the possible mechanisms of sub-optimal responses, and the importance of determining the immune make-up of individual patients prior to prescribing mAb therapy, in the age of precision medicine for asthma.
Idiopathic Pulmonary Fibrosis: An Update on Pathogenesis
Authors: Mei Qianru , Liu Zhe , Zuo He , Yang Zhenhua , Qu Jing
Published: January 2022

Idiopathic pulmonary fibrosis (IPF) is a progressive, lethal fibrotic lung disease that occurs primarily in middle-aged and elderly adults. It is a major cause of morbidity and mortality. With an increase in life expectancy, the economic burden of IPF is expected to continuously rise in the near future. Although the exact pathophysiological mechanisms underlying IPF remain not known. Significant progress has been made in our understanding of the pathogenesis of this devastating disease in last decade. The current paradigm assumes that IPF results from sustained or repetitive lung epithelial injury and subsequent activation of fibroblasts and myofibroblast differentiation. Persistent myofibroblast phenotype contributes to excessive deposition of the extracellular matrix (ECM) and aberrant lung repair, leading to tissue scar formation, distortion of the alveolar structure, and irreversible loss of lung function. Treatments of patients with IPF by pirfenidone and nintedanib have shown significant reduction of lung function decline and slowing of disease progression in patients with IPF. However, these drugs do not cure the disease. In this review, we discuss recent advances on the pathogenesis of IPF and highlight the development of novel therapeutic strategies against the disease.
The Subjective Value of Product Popularity: A Neural Account of How Product Popularity Influences Choice Using a Social and a Quality Focus
Authors: Goedegebure Robert P. G. , Tijssen Irene O. J. M. , van der Laan L. Nynke , van Trijp Hans C. M.
Published: January 2022

Research on social influences often distinguishes between social and quality incentives to ascribe meaning to the value that popularity conveys. This study examines the neural correlates of those incentives through which popularity influences preferences. This research reports an functional magnetic resonance imaging experiment and a behavioral task in which respondents evaluated popular products with three focus perspectives; unspecified focus, focus on social aspects, and focus on quality. The results show that value derived with a social focus reflects inferences of approval and reward value, and positively affects preferences. Value derived with a quality (versus normal) focus reflects inferences of quality and negatively affects preferences. This study provides evidence of two distinct inferential routes on both a neurological level, represented by different regions in the brain, and a behavioral level. These results provide the first evidence that a single popularity cue can in different ways influence the value derived from product popularity.
Social Media for Health Campaign and Solidarity Among Chinese Fandom Publics During the COVID-19 Pandemic
Authors: Jiang Qiaolei , Liu Shiyu , Hu Yue , Xu Jing
Published: January 2022

Background:

As a highly contagious disease, the COVID-19 pandemic has become a serious health threat and psychological burden for the global communities. From the conceptual perspective of affordances, this research examined the role of social media for health campaign and psychological support during the global crisis.

Methods:

Data from both social media and a nationwide survey were collected and analyzed. Face mask-related posts on Sina Weibo from January 1, 2020, to June 30, 2020, were retrieved and studied. Face mask wearing as a well-established preventive measure was identified and examined from hashtag topics. A nationwide survey with a randomized experiment embedded was conducted to further investigate the mobilizing dynamics.

Results:

During the escalation phase in the first half of 2020, the hashtag topic “#national mask campaign#,” initiated by a celebrity, topped the ranking of mask-related topics on Weibo. The findings indicated that prevention activities, solidarity expression, and names of celebrity idols were frequently discussed. With celebrity idols as opinion leaders, millions of fandom publics actively participated in this hashtag health campaign. Results of the nationwide survey show the popularity of fan identity, and the experiment results demonstrate the strong mobilizing power of celebrity idol and fandom community in civic engagement and participation among young Chinese.

Conclusions:

The research demonstrates how the affordances of social media, such as liking, commenting, reposting, and hashtagging can be influential in promoting health behaviors and expressing solidarity. Implications for public health professionals and policymakers to raise awareness and understanding about health campaignsviasocial media are discussed.
Optical-Waveguide Based Tactile Sensing for Surgical Instruments of Minimally Invasive Surgery
Authors: Li Yue , Hu Jian , Cao Danqian , Wang Stephen , Dasgupta Prokar , Liu Hongbin
Published: January 2022

In recent years, with the rapid development of minimally invasive surgery (MIS), the lack of force sensing associated with the surgical instrument used in MIS has been increasingly a desirable technology amongst clinicians. However, it is still an open technical challenge to date since most existing tactile sensing principles are not suitable to small 3-dimensional (3D) curved surfaces often seen in surgical instruments, and as a result multi-point force detection cannot be realized. In this paper, a novel optical waveguide-based sensor was proposed to deal with the above research gap. A sensor prototype for curved surfaces resembling the surface of dissection forceps was developed and experimentally evaluated. The static parameters and dynamic response characteristics of the sensor were measured. Results show that the static hysteresis error is less than 3%, the resolution is 0.026 N, and the repeatability is less than 1.5%. Under a frequency of 12.5 Hz, the sensor could quickly measure the variation of the force signal. We demonstrated that this small and high-precision sensitive sensor design is promising to be used for creating multiple-point tactile sensing for minimally invasive surgical instruments with 3D surfaces.
Exploration of the DARTable Genome- a Resource Enabling Data-Driven NAMs for Developmental and Reproductive Toxicity Prediction
Authors: Janowska-Sejda Elzbieta I. , Adeleye Yeyejide , Currie Richard A.
Published: January 2022

The identification of developmental and reproductive toxicity (DART) is a critical component of toxicological evaluations of chemical safety. Adverse Outcome Pathways (AOPs) provide a framework to describe biological processes leading to a toxic effect and can provide insights in understanding the mechanisms underlying toxicological endpoints and aid the development of new approach methods (NAMs). Integrated approaches to testing and assessment (IATA) can be developed based on AOP knowledge and can serve as pragmatic approaches to chemical hazard characterization using NAMs. However, DART effects remain difficult to predict given the diversity of biological mechanisms operating during ontogenesis and consequently, the considerable number of potential molecular initiating events (MIEs) that might trigger a DART Adverse Outcome (DART AO). Consequently, two challenges that need to be overcome to create an AOP-based DART IATA are having sufficient knowledge of relevant biology and using this knowledge to determine the appropriate selection of cell systems that provide sufficient coverage of that biology. The wealth of modern biological and bioinformatics data can be used to provide this knowledge. Here we demonstrate the utility of bioinformatics analyses to address these questions. We integrated known DART MIEs with gene-developmental phenotype information to curate the hypothetical human DARTable genome (HDG, ∼5 k genes) which represents the comprehensive set of biomarkers for DART. Using network analysis of the human interactome, we show that HDG genes have distinct connectivity compared to other genes. HDG genes have higher node degree with lower neighborhood connectivity, betweenness centralities and average shortest path length. Therefore, HDG is highly connected to itself and to the wider network and not only to their local community. Also, by comparison with the Druggable Genome we show how the HDG can be prioritized to identify potential MIEs based on potential to interact with small molecules. We demonstrate how the HDG in combination with gene expression data can be used to select a panel of relevant cell lines (RD-1, OVCAR-3) for inclusion in an IATA and conclude that bioinformatic analyses can provide the necessary insights and serve as a resource for the development of a screening panel for a DART IATA.