bluuebunny/crossref_metadata_2025 huggingface dataset:
Belimumab or anifrolumab for systemic lupus erythematosus? A risk-benefit assessment
Authors: Kirou Kyriakos A. , Dall`Era Maria , Aranow Cynthia , Anders Hans-Joachim
Published: August 2022

Treatment of systemic lupus erythematosus (SLE) currently employs agents with relatively unselective immunosuppressive properties. However, two target-specific biological drugs have been approved: belimumab (anti-B-cell-activating factor/BAFF) and anifrolumab (anti-interferon alpha receptor-1/IFNAR1). Here, we performed a comparative risk-benefit assessment for both drugs based on the role of BAFF and IFNAR1 in host defense and the pathogenesis of SLE and by considering the available data on safety and efficacy. Due to differences in target expression sites, anti-IFNAR1, but not anti-BAFF, might elicit organ-specific effects, consistent with clinical efficacy data. The IFNAR1 is specifically involved in innate and adaptive antiviral immunity in most cells of the body. Consistent with this observation, the available safety data obtained from patients negatively selected for LN and neuropsychiatric SLE, primary immunodeficiencies, splenectomy and chronic HIV, HBV, HCV infections suggest an increased risk for some viral infections such as varicella zoster and perhaps influenza. In contrast, BAFF is mainly involved in adaptive immune responses in lymphoid tissues, thus anti-BAFF therapy modulates SLE activity and prevents SLE flares without interfering with local innate host defense mechanisms and should only marginally affect immune memory to previous pathogen exposures consistent with the available safety data from SLE patients without chronic HIV, HBV or HCV infections. When using belimumab and anifrolumab, careful patient stratification and specific precautions may minimize risks and maximize beneficial treatment effects for patients with SLE.
Case report: Primary hepatocellular carcinoma with portal vein tumor thrombus characterized by active tumor immune microenvironment achieving a complete response following treatment of combined immunotherapy
Authors: Zhong Kaihang , Xu Yuyan , Cheng Yuan , Wen Yaohong , Cai Lei , He Guolin , Huang Huakun , Fu Shunjun , Zhong Xuefeng , Zheng Yating , Chen Tingting , Huang Mengli , Pan Mingxin
Published: August 2022

Portal vein tumor thrombus (PVTT) is a frequent complication in hepatocellular carcinoma (HCC). HCC patients with PVTT have the characteristics of less treatment tolerance and poor prognosis. Immunotherapy, especially combined immunotherapy, has been successfully used in advanced HCC. However, there are no recognized universally indicators that can predict response or resistance to immunotherapy for HCC. Herein, we reported a 58-year-old HCC patient with PVTT, cirrhosis and chronic viral hepatitis, who achieved complete response (CR) after combined immunotherapy (camrelizumab combined with sorafenib or regorafenib), according to his high enrichment of tumor-infiltrating immune cells and tertiary lymphoid structure (TLS). In this case, we revealed the characteristics of the baseline tumor immune microenvironment (TIME) in a HCC patient who responded well to combined immunotherapy, suggesting that TIME can be used to assist in clinical decision making of immunotherapy for HCC.
A review of non-destructive methods for the detection tiny defects within organic insulating materials
Authors: Zhang Xinlong , Cheng Li , Liu Yunfan , Tao Bo , Wang Jiuyi , Liao Ruijin
Published: August 2022

In recent years, solid organic materials such as silicone rubber and epoxy resin have been widely used in electrical equipment due to their excellent insulation properties. However, as a result of manufacturing and design flaws as well as aging issues during operation, the insulating materials in the linked state no longer fit tightly and tiny structural defects (defect size less than 10 mm) develop, such as debonding at the composite interface, pores or cracks within the insulating material, etc. Tiny defects are prone to partial discharges and breakdowns, compromising the safety of high-voltage power equipment, particularly when subjected to strong electric fields. Therefore, it is necessary to carry out non-destructive testing (NDT) for such tiny defects. Such defects are small in size, easily buried in the material, and even some are wrapped in metal, which in turn requires very high detection accuracy, but traditional methods are difficult to achieve, so NDT technologies for tiny defects within insulating materials have become a research hotspot in the field of electric power in recent years. This paper firstly introduces the sources of tiny defects in solid organic insulating materials for electrical equipment. Secondly, the harm caused by structural defects is elaborated. Finally, emerging NDT methods and their advantages and limitations in defect detection are described in detail. The review aims to provide the reader with a comprehensive overview of most of the NDT techniques used in the detection of tiny defects within solid organic insulating materials for electrical equipment and their most salient features.
A Case Report of Two Kala-azar Cases in China Diagnosed by Metagenomic Next-Generation Sequencing
Authors: Gao Hongguang , Wang Jing , Zhang Shu , Li Tian
Published: August 2022

Background

Leishmaniasis being a local disease, as kala-azar this particular form is a visceral form. It is transmitted by sandflies, and is a parasitic disease involving the reticuloendothelial system of mononuclear macrophages. Due to its poor prognosis and high fatality rate, the fatality rate of patients without effective treatment can exceed 95%. Thereby, early diagnosis and treatment can significantly improve its prognosis. The metagenomic next-generation sequencing (mNGS) has the advantage of being able to find pathogens that cannot be detected by traditional methods. More importantly, it can conduct nucleic acid detection of pathogens covering a wide range in a short time. For infectious diseases like kala-azar, which is clinically complicated and difficult, mNGS detection provides a basis for accurate etiological diagnosis.

Case Report

We report 2 cases of kala-azar in West China Hospital, Chengdu, China. The first case is a 47-year-old male patient who had recurrent fever for 4 months, accompanied by reduction of red blood cell, white blood cell, and blood platelet. He was detected by mNGS and clinically diagnosed as kala-azar (Leishmania detection), finally died of multiple organ failure. The second patient was a 15-year-old male who had fever for more than 10 days. He was detected by mNGS and clinically diagnosed as kala-azar (Leishmania detection). He recovered and discharged quickly after treatment with sodium stibogluconate.

Conclusion

Efforts should be made to improve early etiological diagnosis in order to improve patient prognosis. mNGS detection is beneficial to the diagnosis and treatment of infectious diseases with unknown causes in the early stage of emergency treatment.
The multifaceted phenotypic and genotypic spectrum of type-IV-collagen-related nephropathy—A human genetics department experience
Authors: Ćomić Jasmina , Riedhammer Korbinian M. , Günthner Roman , Schaaf Christian W. , Richthammer Patrick , Simmendinger Hannes , Kieffer Donald , Berutti Riccardo , Tasic Velibor , Abazi-Emini Nora , Nushi-Stavileci Valbona , Putnik Jovana , Stajic Nataša , Lungu Adrian , Gross Oliver , Renders Lutz , Heemann Uwe , Braunisch Matthias C. , Meitinger Thomas , Hoefele Julia
Published: August 2022

Disease-causing variants in COL4A3-5 are associated with type-IV-collagen-related nephropathy, a genetically and phenotypically multifaceted disorder comprising Alport syndrome (AS) and thin basement membrane nephropathy (TBMN) and autosomal, X-linked and a proposed digenic inheritance. Initial symptoms of individuals with AS are microscopic hematuria followed by proteinuria leading to kidney failure (90% on dialysis < age 40 years). In contrast, individuals with TBMN, an outdated histology-derived term, present with microscopic hematuria, only some of them develop kidney failure (>50 years of age). An early diagnosis of type-IV-collagen-related nephropathy is essential for optimized therapy and slowing of the disease. Sixty index cases, in whom exome sequencing had been performed and with disease-causing variant(s) in COL4A3-5, were evaluated concerning their clinical tentative diagnosis and their genotype. Of 60 reevaluated individuals with type-IV-collagen-related nephropathy, 72% had AS, 23% TBMN and 5% focal segmental glomerulosclerosis (FSGS) as clinical tentative diagnosis. The FSGS cases had to be re-classified as having type-IV-collagen-related nephropathy. Twelve percent of cases had AS as clinical tentative diagnosis and a monoallelic disease-causing variant in COL4A3/4 but could not be classified as autosomal dominant AS because of limited or conflicting clinical data. This study illustrates the complex clinical and genetic picture of individuals with a type IV-collagen-related nephropathy indicating the need of a refined nomenclature and the more interdisciplinary teamwork of clinicians and geneticists as the key to optimized patient care.
Lymph node metastases outside tumor-bearing lobes and/or segments in non–small cell lung cancer
Authors: Han Lu , Jia Hui , Song Pingping , Liu Xibin , Wang Zhendan , Zhang Dujian
Published: August 2022

Objective

Hilar and lung lymph node metastases (N1) are defined as ipsilateral bronchial and intrapulmonary lymph nodes. However, the cleaning standards for ipsilateral bronchial lymph nodes in different lobes and segments within the same lobe in segmentectomy are not clearly defined.

Materials and methods

Sixty-six patients undergoing pulmonary resection for the treatment of lung cancer were evaluated. Intraoperatively visible non-tumor-bearing lobe (NTBL) and post-operatively non-tumor-bearing segment (NTBS) lymph nodes were removed and analyzed. The associations between the NTBL LNs and clinicopathological characteristics were analyzed.

Results

Non-tumor-bearing lobe LNs metastases were found in 8 (12.1%) of the 66 patients, NTBS LNs metastasis were not found (0/13). The presence of NTBL metastases was significantly associated with age (<60 years vs. ≥60 years, P = 0.037), differentiation (Grade 1 well differentiated vs. Grade 2 moderately differentiated vs. Grade 3 poorly differentiated, P = 0.012), CAT-scan-findings of Mediastinal and hilar lymph nodes metastasis (node-positive vs. node-negative, P = 0.022), pN stage (N0 vs. N1 vs. N2, P = 0.003) and p stage (I vs. II vs. III, P = 0.009). Multivariate logistic analysis showed that tumor differentiation (P = 0.048, HR 6.229; 95% CI 1.016–38.181) and pN (P = 0.024, HR 5.099; 95% CI 1.245–20.878) were statistically significant predictors.

Conclusions

Lobar lymph node metastasis of NTBL occurs frequently in patients with NSCLC, but lymph node metastases in NTBS LNs are rare. Advanced age, poorly differentiated and N1 and N2 status of CAT-scan-findings were independent risk factors for the involvement of the NTBL lobar lymph nodes. Although lymph node metastases in NTBS are rare, further investigation of the need to dissect is required.
Spectinomycin resistance in Lysobacter enzymogenes is due to its rRNA target but also relies on cell-wall recycling and purine biosynthesis
Authors: Yu Menghao , Zhao Youfu
Published: August 2022

Resistance to spectinomycin emerged after widely used for treatment of gonorrhea. Previous studies revealed that Lysobacter enzymogenes strain C3 (LeC3) exhibited elevated level of intrinsic resistance to spectinomycin. In this study, we screened a Tn5 transposon mutant library of LeC3 to elucidate the underlying molecular mechanisms of spectinomycin resistance. Insertion sites in 15 out of 19 mutants recovered with decreased spectinomycin resistance were located on two ribosomal RNA operons at different loci, indicating the pivotal role of ribosomal RNAs in conferring spectinomycin resistance in L. enzymogenes. The other mutants harbored mutations in the tuf, rpoD, mltB, and purB genes. Among them, the tuf and rpoD genes, respectively, encode a translation elongation factor Tu and an RNA polymerase primary sigma factor. They both contribute to protein biosynthesis, where ribosomal RNAs play essential roles. The mltB gene, whose product is involved in cell-wall recycling, was not only associated with resistance against spectinomycin, but also conferred resistance to osmotic stress and ampicillin. In addition, mutation of the purB gene, for which its product is involved in the biosynthesis of inosine and adenosine monophosphates, led to decreased spectinomycin resistance. Addition of exogenous adenine at lower concentration in medium restored the growth deficiency in the purB mutant and increased bacterial resistance to spectinomycin. These results suggest that while cell-wall recycling and purine biosynthesis might contribute to spectinomycin resistance, target rRNAs play critical role in spectinomycin resistance in L. enzymogenes.
Exploring the misfolding and self-assembly mechanism of TTR (105–115) peptides by all-atom molecular dynamics simulation
Authors: Zhang Yuqi , Zhu Yanyan , Yue Haiyan , Zhao Qingjie , Li Huiyu
Published: August 2022

Pathological aggregation of essentially dissociative Transthyretin (TTR) monomers protein, driven by misfolded and self-interaction, is connected with Amyloid Transthyretin amyloidosis (ATTR) disease. The TTR monomers protein contains several fragments that tend to self-aggregate, such as residue 105–115 sequence [TTR (105–115)]. However, the misfolding and aggregation mechanisms of TTR are still unknown. In this study, we explored the misfolding and self-assembly of TTR (105–115) peptides by all-atom molecular dynamics simulation. Our results indicated that the conformation of the two-peptides appears unstable. In the tetramerization and hexamerization simulations, the results are reversed. When the number of peptides increases, the probability and the length of β-Sheet contents increase. Our results show that that the four- and six-peptides both can form β-Barrel intermediates and then aggregate into fibers. The critical nucleation for the formation of fibril should be larger than four-peptides. The interactions between hydrophobic residues I107-L111 play an important role in the formation of stable fibrils at an early stage. Our results on the structural ensembles and early aggregation dynamics of TTR (105–115) will be useful to comprehend the nucleation and fibrillization of TTR (105–115).
Abnormal cortical atrophy and functional connectivity are associated with depression in Parkinson’s disease
Authors: Yin Weifang , Li Anming , Yang Baiyuan , Gao Chao , Hu Yanfei , Luo Zhenglong , Li Yuxia , Zhu Yongyun , Zhou Chuanbin , Ren Hui , Li Shimei , Yang Xinglong
Published: August 2022

Objective

This study aimed to investigate the association of altered cortical thickness and functional connectivity (FC) with depression in Parkinson’s disease (PD).

Materials and methods

A total of 26 non-depressed PD patients (PD-ND), 30 PD patients with minor depression (PD-MnD), 32 PD patients with major depression (PD-MDD), and 30 healthy controls (HC) were enrolled. Differences in cortical thickness among the four groups were assessed, and the results were used to analyze FC differences in regions of cortical atrophy. Binary logistic regression and receiver operating characteristic (ROC) curve analyses were also performed to identify clinical features and neuroimaging biomarkers that might help in the prediction of PD-MDD.

Results

Patients with PD-MDD showed decreased cortical thickness compared to patients with PD-ND in the left superior temporal and right rostral middle frontal gyri (RMFG), as well as weak FC between the left superior temporal gyrus and right cerebellum posterior lobe and between right RMFG and right inferior frontal gyrus and insula. The combination of cortical thickness, FC, and basic clinical features showed strong potential for predicting PD-MDD based on the area under the ROC curve (0.927, 95% CI 0.854–0.999, p < 0.001).

Conclusion

Patients with PD-MDD show extensive cortical atrophy and FC alterations, suggesting that cortical thickness and FC may be neuroimaging-based diagnostic biomarkers for PD-MDD.
Complement component 3 and complement factor H protein levels are altered in brain tissues from people with human immunodeficiency virus: A pilot study
Authors: Fields Jerel Adam , Swinton Mary , Sundermann Erin E. , Scrivens Nicholas , Vallee Kaylie-Anna Juliette , Moore David J.
Published: August 2022

People with HIV (PWH) continue to suffer from dysfunction of the central nervous system, as evidenced by HIV-associated neurocognitive disorder (HAND), despite antiretroviral therapy and suppressed viral loads. As PWH live longer they may also be at risk of age-related neurodegenerative diseases such Alzheimer’s disease (AD) and its precursor, amnestic mild cognitive impairment (aMCI). The complement system is associated with deposition of AD-related proteins such as beta amyloid (Aβ), neuroinflammation, and neurological dysfunction in PWH. Complement component 3 (C3) is a key protagonist in the complement cascade and complement factor H (CFH) is an antagonist of C3 activity. We investigated the relationship between C3 and CFH levels in the brain and Aβ plaques and neurological dysfunction in 22 PWH. We analyzed by immunoblot C3 and CFH protein levels in frontal cortex (FC) and cerebellum (CB) brain specimens from PWH previously characterized for Aβ plaque deposition. C3 and CFH protein levels were then correlated with specific cognitive domains. C3 protein levels in the FC were significantly increased in brains with Aβ plaques and in brains with HAND compared to controls. In the CB, C3 levels trended higher in brains with Aβ plaques. Overall C3 protein levels were significantly higher in the FC compared to the CB, but the opposite was true for CFH, having significantly higher levels of CFH protein in the CB compared to the FC. However, only CFH in the FC showed significant correlations with specific domains, executive function and motor performance. These findings corroborate previous results showing that complement system proteins are associated with HAND and AD neuropathogenesis.
Conscious awareness of a visuo-proprioceptive mismatch: Effect on cross-sensory recalibration
Authors: Hsiao Anna , Lee-Miller Trevor , Block Hannah J.
Published: August 2022

The brain estimates hand position using vision and position sense (proprioception). The relationship between visual and proprioceptive estimates is somewhat flexible: visual information about the index finger can be spatially displaced from proprioceptive information, resulting in cross-sensory recalibration of the visual and proprioceptive unimodal position estimates. According to the causal inference framework, recalibration occurs when the unimodal estimates are attributed to a common cause and integrated. If separate causes are perceived, then recalibration should be reduced. Here we assessed visuo-proprioceptive recalibration in response to a gradual visuo-proprioceptive mismatch at the left index fingertip. Experiment 1 asked how frequently a 70 mm mismatch is consciously perceived compared to when no mismatch is present, and whether awareness is linked to reduced visuo-proprioceptive recalibration, consistent with causal inference predictions. However, conscious offset awareness occurred rarely. Experiment 2 tested a larger displacement, 140 mm, and asked participants about their perception more frequently, including at 70 mm. Experiment 3 confirmed that participants were unbiased at estimating distances in the 2D virtual reality display. Results suggest that conscious awareness of the mismatch was indeed linked to reduced cross-sensory recalibration as predicted by the causal inference framework, but this was clear only at higher mismatch magnitudes (70–140 mm). At smaller offsets (up to 70 mm), conscious perception of an offset may not override unconscious belief in a common cause, perhaps because the perceived offset magnitude is in range of participants’ natural sensory biases. These findings highlight the interaction of conscious awareness with multisensory processes in hand perception.
Moxibustion for primary dysmenorrhea: A resting-state functional magnetic resonance imaging study exploring the alteration of functional connectivity strength and functional connectivity
Authors: Yang Han , Li Xiang , Guo Xiao-li , Zhou Jun , Shen Zhi-fu , Liu Li-ying , Wei Wei , Yang Lu , Yu Zheng , Chen Jiao , Liang Fan-rong , Yu Si-yi , Yang Jie
Published: August 2022

Introduction

Primary dysmenorrhea (PDM) is a common gynecological disease and chronic pain disorder. Moxibustion, a form of traditional Chinese medicine therapy, has proven to be effective for PDM. However, the central mechanisms of PDM and moxibustion for PDM are still unclear. This study aims to explore the potential central mechanism of PDM and clarify the possible mechanism of moxibustion for relieving pain.

Materials and methods

A total of 23 PDM patients and 23 matched healthy controls (HCs) were enrolled. For PDM patients, resting-state functional magnetic resonance imaging (rs-fMRI) data were collected pre- and post-moxibustion treatment of 3 consecutive menstrual cycles, respectively. For HCs, rs-fMRI data were collected in the baseline. The resting-state functional connectivity strength (rs-FCS) analysis and the resting-state functional connectivity (rs-FC) analysis based on the region of interest (ROI) were combined to be conducted.

Results

Compared to HCs, PDM patients showed weaker rs-FCS in the left inferior frontal gyrus (IFG). After the moxibustion treatment, rs-FCS in the left IFG was increased with clinical improvement. Then, the left IFG was chosen as ROI, and the rs-FC analysis was conducted. It showed that the left IFG rs-FC in the bilateral anterior cingulate cortex (ACC)/middle cingulate cortex (MCC), the left posterior cingulate cortex (PCC)/precuneus (PCU), and the left parahippocampal gyrus (PHG) decreased after moxibustion treatment, most of which belong to the default mode network (DMN).

Conclusion

Our results highlight the role of the left IFG and the DMN in PDM. Specifically, the central mechanism of moxibustion for analgesia may be related to modulating the disorders of the reappraisal and processing of pain stimuli through influencing the cognition of pain.
Transcriptome analysis of microRNAs, circRNAs, and mRNAs in the dorsal root ganglia of paclitaxel-induced mice with neuropathic pain
Authors: Mao Qingxiang , Tian Lixia , Wei Jianxiong , Zhou Xiaoqiong , Cheng Hong , Zhu Xuan , Li Xiang , Gao Zihao , Zhang Xi , Liang Lingli
Published: August 2022

The microtubule-stabilizing drug paclitaxel (PTX) is a chemotherapeutic agent widely prescribed for the treatment of various tumor types. The main adverse effect of PTX-mediated therapy is chemotherapy-induced peripheral neuropathy (CIPN) and neuropathic pain, which are similar to the adverse effects associated with other chemotherapeutic agents. Dorsal root ganglia (DRG) contain primary sensory neurons; any damage to these neurons or their axons may lead to neuropathic pain. To gain molecular and neurobiological insights into the peripheral sensory system under conditions of PTX-induced neuropathic pain, we used transcriptomic analysis to profile mRNA and non-coding RNA expression in the DRGs of adult male C57BL/6 mice treated using PTX. RNA sequencing and in-depth gene expression analysis were used to analyze the expression levels of 67,228 genes. We identified 372 differentially expressed genes (DEGs) in the DRGs of vehicle- and PTX-treated mice. Among the 372 DEGs, there were 8 mRNAs, 3 long non-coding RNAs (lncRNAs), 16 circular RNAs (circRNAs), and 345 microRNAs (miRNAs). Moreover, the changes in the expression levels of several miRNAs and circRNAs induced by PTX have been confirmed using the quantitative polymerase chain reaction method. In addition, we compared the expression levels of differentially expressed miRNAs and mRNA in the DRGs of mice with PTX-induced neuropathic pain against those evaluated in other models of neuropathic pain induced by other chemotherapeutic agents, nerve injury, or diabetes. There are dozens of shared differentially expressed miRNAs between PTX and diabetes, but only a few shared miRNAs between PTX and nerve injury. Meanwhile, there is no shared differentially expressed mRNA between PTX and nerve injury. In conclusion, herein, we show that treatment with PTX induced numerous changes in miRNA expression in DRGs. Comparison with other neuropathic pain models indicates that DEGs in DRGs vary greatly among different models of neuropathic pain.
DNA damage response and repair genes in advanced bone and soft tissue sarcomas: An 8-gene signature as a candidate predictive biomarker of response to trabectedin and olaparib combination
Authors: Merlini Alessandra , Centomo Maria Laura , Ferrero Giulio , Chiabotto Giulia , Miglio Umberto , Berrino Enrico , Giordano Giorgia , Brusco Silvia , Pisacane Alberto , Maldi Elena , Sarotto Ivana , Capozzi Federica , Lano Cristina , Isella Claudio , Crisafulli Giovanni , Aglietta Massimo , Dei Tos Angelo Paolo , Sbaraglia Marta , Sangiolo Dario , D’Ambrosio Lorenzo , Bardelli Alberto , Pignochino Ymera , Grignani Giovanni
Published: August 2022

Background

Advanced and unresectable bone and soft tissue sarcomas (BSTS) still represent an unmet medical need. We demonstrated that the alkylating agent trabectedin and the PARP1-inhibitor olaparib display antitumor activity in BSTS preclinical models. Moreover, in a phase Ib clinical trial (NCT02398058), feasibility, tolerability and encouraging results have been observed and the treatment combination is currently under study in a phase II trial (NCT03838744).

Methods

Differential expression of genes involved in DNA Damage Response and Repair was evaluated by Nanostring® technology, extracting RNA from pre-treatment tumor samples of 16 responder (≥6-month progression free survival) and 16 non-responder patients. Data validation was performed by quantitative real-time PCR, RNA in situ hybridization, and immunohistochemistry. The correlation between the identified candidate genes and both progression-free survival and overall survival was investigated in the publicly available dataset “Sarcoma (TCGA, The Cancer Genome Atlas)”.

Results

Differential RNA expression analysis revealed an 8-gene signature (CDKN2A, PIK3R1, SLFN11, ATM, APEX2, BLM, XRCC2, MAD2L2) defining patients with better outcome upon trabectedin+olaparib treatment. In responder vs. non-responder patients, a significant differential expression of these genes was further confirmed by RNA in situ hybridization and by qRT-PCR and immunohistochemistry in selected experiments. Correlation between survival outcomes and genetic alterations in the identified genes was shown in the TCGA sarcoma dataset.

Conclusions

This work identified an 8-gene expression signature to improve prediction of response to trabectedin+olaparib combination in BSTS. The predictive role of these potential biomarkers warrants further investigation.
The safety of neoadjuvant chemotherapy combined with non-tube nofasting fast-track surgery for esophageal carcinoma
Authors: Zheng Yan , Hao Wentao , Li Yin , Liu Xianben , Wang Zongfei , Sun Haibo , Liu Shilei , Xing Wenqun
Published: August 2022

Our non-tube no fasting (early oral feeding and no nasogastric tube) fast-track surgery (FTS) was safe and effective to combine with neoadjuvant chemotherapy for McKeown minimally invasive esophagectomy. In addition, the two groups were similar in terms of the recovery time, hospital discharge day, and early resumption of oral feeding.

Objectives

To evaluate the safety of early oral feeding (EOF) combined with neoadjuvant chemotherapy (NAC) of esophagectomy.

Summary Background Data

Our non-tube no fasting (early oral feeding and no nasogastric tube) fast-track surgery (FTS) was safe and effective for primary surgery esophageal cancer patients.

Methods

We retrospectively evaluated consecutive patients who underwent non-tube no fasting and McKeown minimally invasive (MIE). They were divided into two groups: one received NAC, and the other received primary surgery. Complications after the operation, postoperative CRG complications, operative time, operative bleeding, and length of stay were evaluated.

Results

Between 01/2014 and 12/2017, there hundred and eighty two consecutive patients underwent MIE with total two-field lymphadenectomy under the non-tube no fasting fast-track surgery program. A total of 137 patients received NAC, and 245 accepted primary surgery. Propensity score matching was used to compare NAC patients with 62 matched patients from each group. The NAC group had a similar number of total complications as the primary surgery group (32.26% in the primary surgery group vs. 25.81% in the NAC group; p=0.429) and had the same median postoperative hospitalization duration (8 days, p=0.723).

Conclusions

After McKeown MIE, the patients receiving NAC combined with “non-tube no fasting” FTS had a similar incidence of postoperative complications outcomes as those without NAC. In addition, the two groups were similar in terms of the recovery time, hospital discharge day, and early resumption of oral feeding.
Adjuvant chemotherapy may improve long-term outcomes in stage IB non-small cell lung cancer patients with previous malignancies: A propensity score-matched analysis
Authors: Zhou Ke , Zhao Yaqin , Liang Linchuan , Cao Jie , Lin Huahang , Peng Zhiyu , Mei Jiandong
Published: August 2022

Background

Routine administration of adjuvant chemotherapy for stage IB non-small cell lung cancer (NSCLC) remains controversial. To our knowledge, no available studies have assessed the outcomes of chemotherapy in patients with stage IB NSCLC who had prior malignancies.

Methods

Patients with pathological stage IB NSCLC with previous malignancies who underwent surgery between 2004 and 2015 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. The patients were categorized into chemotherapy and observation group based on whether they received adjuvant chemotherapy. Propensity score matching was performed to reduce confounding bias, and Kaplan–Meier curves and log-rank tests were used to compare overall survival (OS) and cancer-specific survival (CSS) between the two groups. Subgroup analyses of the matched cohorts were then conducted to evaluate the relationship between clinical features and chemotherapy.

Results

A total of 894 eligible patients were identified; 90 (10.1%) patients received postoperative chemotherapy. Patients who received adjuvant chemotherapy obtained obvious OS benefits compared with those who received observation alone (HR = 0.68, 95% CI: 0.48–0.97, P = 0.031). In addition, the 5-year OS rate and median OS time in the chemotherapy group were higher and longer, respectively. Although chemotherapy offered no obvious benefits for CSS (HR = 0.80, 95% CI: 0.57–1.14, P = 0.35), patients who received chemotherapy showed a better 5-year CSS rate. On subgroup analyses, a chemotherapy advantage was observed in advanced age (≥65 years, HR = 0.62, 95% CI: 0.38–0.99, P = 0.045). The same chemotherapy advantages were observed in patients diagnosed with higher histological grades (poorly differentiated to undifferentiated) (HR = 0.56, 95% CI: 0.33–0.96, P = 0.033) and tumor sizes >3.1–4 cm (HR = 0.57, 95% CI: 0.37–0.87, P = 0.010). Interestingly, NSCLC patients with previous malignancies originating from the kidney and bladder (HR = 0.34, 95% CI: 0.12–0.99, P = 0.049) showed a chemotherapy advantage. The same chemotherapy advantages were observed in patients diagnosed with NSCLC within 3 to 5 years after prior cancers (HR = 0.39, 95% CI: 0.16–0.98, P = 0.044) and with localized SEER stage of prior cancers (HR = 0.49, 95% CI: 0.29–0.86, P = 0.012).

Conclusion

These findings indicate that adjuvant chemotherapy may improve long-term outcomes for stage IB NSCLC patients with previous malignancies. It is recommended that physicians consider the clinical features of previous cancers when making adjuvant chemotherapy decisions for these patients.
Mass spectrometric analysis of TRPM6 and TRPM7 from small intestine of omeprazole-induced hypomagnesemic rats
Authors: Kampuang Nattida , Thongon Narongrit
Published: August 2022

Disruption of small intestinal Mg2+ absorption has been reported as the underlying mechanism of proton pump inhibitor-induced hypomagnesemia (PPIH); hence, this study evaluated the expression, localization, phosphorylation, and oxidation of transient receptor potential melastatin 6 (TRPM6) and TRPM7 in the small intestine of rats subjected to PPIH. The expression and localization of cyclin M4 (CNNM4) was also analyzed. We show that, compared to control rats, membrane expression of the TRPM6/7 heterodimer and TRPM7 was markedly lower in the duodenum and the jejunum of PPIH rats; in contrast, expression of membrane TRPM6 and CNNM4 was higher in these organs. Mass spectrometric analysis of TRPM6 demonstrated hyper-phosphorylation, especially T1851, and hyper-oxidation at M1755, both of which can suppress its channel permeability. Further, hypo-phosphorylation of S141 and the dimerization motif domain of TRPM6 in PPIH rats might be involved in lower TRPM6/7 heterodimer expression. Hypo-phosphorylation, especially at S138 and S1360 in TRPM7 from PPIH rats disrupted stability of TRPM7 at the cell membrane; hyper-oxidation of TRPM7 was also observed. These results help explain the mechanism underlying the disruption of small intestinal Mg2+ absorption in PPIH.
Tumor-infiltrating immune cells based TMEscore and related gene signature is associated with the survival of CRC patients and response to fluoropyrimidine-based chemotherapy
Authors: Guo Xian-Wen , Li Si-Qi , Lei Rong-E , Ding Zhen , Hu Bang-li , Lin Rong
Published: August 2022

Background

Tumor-infiltrating immune cells (TIICs) are associated with chemotherapy response. This study aimed to explore the prognostic value of a TIIC-related tumor microenvironment score (TMEscore) in patients with colorectal cancer (CRC) who underwent chemotherapy and construct a TMEscore-related gene signature to determine its predictive value.

Methods

Gene profiles of patients who underwent fluoropyrimidine-based chemotherapy were collected, and their TIIC fractions were calculated and clustered. Differentially expressed genes (DEGs) between clusters were used to calculate the TMEscore. The association between the TMEscore, chemotherapy response, and survival rate was analyzed. Machine learning methods were used to identify key TMEscore-related genes, and a gene signature was constructed to verify the predictive value.

Results

Two clusters based on the TIIC fraction were identified, and the TMEscore was calculated based on the DEGs of the two clusters. The TMEscore was higher in patients who responded to chemotherapy than in those who did not, and was associated with the survival rate of patients who underwent chemotherapy. Three machine learning methods, support vector machine (SVM), decision tree (DT), and Extreme Gradient Boosting (XGBoost), identified three TMEscore-related genes (ADH1C, SLC26A2, and NANS) associated with the response to chemotherapy. A TMEscore-related gene signature was constructed, and three external cohorts validated that the gene signature could predict the response to chemotherapy. Five datasets and clinical samples showed that the expression of the three TMEscore-related genes was increased in tumor tissues compared to those in control tissues.

Conclusions

The TIIC-based TMEscore was associated with the survival of CRC patients who underwent fluoropyrimidine-based chemotherapy, and predicted the response to chemotherapy. The TMEscore-related gene signature had a better predictive value for response to chemotherapy than for survival.
Patient selection, inter-fraction plan robustness and reduction of toxicity risk with deep inspiration breath hold in intensity-modulated radiotherapy of locally advanced non-small cell lung cancer
Authors: Fjellanger Kristine , Rossi Linda , Heijmen Ben J. M. , Pettersen Helge Egil Seime , Sandvik Inger Marie , Breedveld Sebastiaan , Sulen Turid Husevåg , Hysing Liv Bolstad
Published: August 2022

Background

State-of-the-art radiotherapy of locally advanced non-small cell lung cancer (LA-NSCLC) is performed with intensity-modulation during free breathing (FB). Previous studies have found encouraging geometric reproducibility and patient compliance of deep inspiration breath hold (DIBH) radiotherapy for LA-NSCLC patients. However, dosimetric comparisons of DIBH with FB are sparse, and DIBH is not routinely used for this patient group. The objective of this simulation study was therefore to compare DIBH and FB in a prospective cohort of LA-NSCLC patients treated with intensity-modulated radiotherapy (IMRT).

Methods

For 38 LA-NSCLC patients, 4DCTs and DIBH CTs were acquired for treatment planning and during the first and third week of radiotherapy treatment. Using automated planning, one FB and one DIBH IMRT plan were generated for each patient. FB and DIBH was compared in terms of dosimetric parameters and NTCP. The treatment plans were recalculated on the repeat CTs to evaluate robustness. Correlations between ΔNTCPs and patient characteristics that could potentially predict the benefit of DIBH were explored.

Results

DIBH reduced the median Dmean to the lungs and heart by 1.4 Gy and 1.1 Gy, respectively. This translated into reductions in NTCP for radiation pneumonitis grade ≥2 from 20.3% to 18.3%, and for 2-year mortality from 51.4% to 50.3%. The organ at risk sparing with DIBH remained significant in week 1 and week 3 of treatment, and the robustness of the target coverage was similar for FB and DIBH. While the risk of radiation pneumonitis was consistently reduced with DIBH regardless of patient characteristics, the ability to reduce the risk of 2-year mortality was evident among patients with upper and left lower lobe tumors but not right lower lobe tumors.

Conclusion

Compared to FB, DIBH allowed for smaller target volumes and similar target coverage. DIBH reduced the lung and heart dose, as well as the risk of radiation pneumonitis and 2-year mortality, for 92% and 74% of LA-NSCLC patients, respectively. However, the advantages varied considerably between patients, and the ability to reduce the risk of 2-year mortality was dependent on tumor location. Evaluation of repeat CTs showed similar robustness of the dose distributions with each technique.
Characterization of genetic predisposition to molecular subtypes of breast cancer in Brazilian patients
Authors: Paixão Daniele , Torrezan Giovana Tardin , Santiago Karina Miranda , Formiga Maria Nirvana , Ahuno Samuel Terkper , Dias-Neto Emmanuel , Tojal da Silva Israel , Foulkes William D. , Polak Paz , Carraro Dirce Maria
Published: August 2022

Introduction

BRCA1 and BRCA2 germline pathogenic variants (GPVs) account for most of the 5-10% of breast cancer (BC) that is attributable to inherited genetic variants. BRCA1 GPVs are associated with the triple negative subtype, whereas BRCA2 GPVs are likely to result in higher grade, estrogen-receptor positive BCs. The contribution of other genes of high and moderate risk for BC has not been well defined and risk estimates to specific BC subtypes is lacking, especially for an admixed population like Brazilian.

Objective

The aim of this study is to evaluate the value of a multigene panel in detecting germline mutations in cancer-predisposing genes for Brazilian BC patients and its relation with molecular subtypes and the predominant molecular ancestry.

Patients and methods

A total of 321 unrelated BC patients who fulfilled NCCN criteria for BRCA1/2 testing between 2016-2018 were investigated with a 94-genes panel. Molecular subtypes were retrieved from medical records and ancestry-specific variants were obtained from off-target reads obtained from the sequencing data.

Results

We detected 83 GPVs in 81 patients (positivity rate of 25.2%). Among GPVs, 47% (39/83) were identified in high-risk BC genes (BRCA1/2, PALB2 and TP53) and 18% (15/83) in moderate-penetrance genes (ATM, CHEK2 and RAD51C). The remainder of the GPVs (35% - 29/83), were identified in lower-risk genes. As for the molecular subtypes, triple negative BC had a mutation frequency of 31.6% (25/79), with predominance in BRCA1 (12.6%; 10/79). Among the luminal subtypes, except Luminal B HER2-positive, 18.7% (29/155) had GPV with BRCA1/2 genes contributing 7.1% (11/155) and non-BRCA1/2 genes, 12.9% (20/155). For Luminal B HER2-positive subtype, 40% (16/40) had GPVs, with a predominance of ATM gene (15% - 6/40) and BRCA2 with only 2.5% (1/40). Finally, HER2-enriched subtype presented a mutation rate of 30.8% (4/13) with contribution of BRCA2 of 7.5% (1/13) and non-BRCA1/2 of 23% (3/13). Variants of uncertain significance (VUS) were identified in 77.6% (249/321) of the patients and the number of VUS was increased in patients with Asian and Native American ancestry.

Conclusion

The multigene panel contributed to identify GPVs in genes other than BRCA1/2, increasing the positivity of the genetic test from 9.6% (BRCA1/2) to 25.2% and, considering only the most clinically relevant BC predisposing genes, to 16.2%. These results indicate that women with clinical criteria for hereditary BC may benefit from a multigene panel testing, as it allows identifying GPVs in genes that directly impact the clinical management of these patients and family members.
Perspectives: Neonatal acute kidney injury (AKI) in low and middle income countries (LMIC)
Authors: McCulloch Mignon I. , Adabayeri Victoria M. , Goka Selasie , Khumalo Tholang S. , Lala Nilesh , Leahy Shannon , Ngubane-Mwandla Nokukhanya , Nourse Peter J. , Nyann Beatrice I. , Petersen Karen L. , Levy Cecil S.
Published: August 2022

Neonatal AKI (NAKI) remains a challenge in low- and middle-income countries (LMICs). In this perspective, we address issues of diagnosis and risk factors particular to less well-resourced regions. The conservative management pre-kidney replacement therapy (pre-KRT) is prioritized and challenges of KRT are described with improvised dialysis techniques also included. Special emphasis is placed on ethical and palliation principles.
Immune function in newborns with in-utero exposure to anti-TNFα therapy
Authors: Weiss Batia , Ben-Horin Shomron , Lev Atar , Broide Efrat , Yavzori Miri , Lahat Adi , Kopylov Uri , Picard Orit , Eliakim Rami , Ron Yulia , Avni-Biron Irit , Yerushalmy-Feler Anat , Assa Amit , Somech Raz , Bar-Gil Shitrit Ariella
Published: August 2022

Background and aim

Anti-TNFα is measurable in infants exposed in utero up to 12 months of age. Data about the exposure effect on the infant’s adaptive immunity are limited. We aimed to prospectively evaluate the distribution and function of T and B cells, in infants of females with inflammatory bowel disease, in utero exposed to anti-TNFα or azathioprine.

Methods

A prospective multi-center study conducted 2014–2017. Anti-TNFα levels were measured in cord blood, and at 3 and 12 months. T-cell repertoire and function were analyzed at 3 and 12 months by flow-cytometry, expression of diverse T cell receptors (TCR) and T-cell receptor excision circles (TREC) quantification assay. Serum immunoglobulins and antibodies for inactivated vaccines were measured at 12 months. Baseline clinical data were retrieved, and 2-monthly telephonic interviews were performed regarding child infections and growth.

Results

24 pregnant females, age 30.6 (IQR 26.5–34.5) years were recruited, 20 with anti-TNFα (infliximab 8, adalimumab 12), and 4 with azathioprine treatment. Cord blood anti-TNFα was higher than maternal blood levels [4.3 (IQR 2.3–9.2) vs. 2.5 (IQR 1.3–9.7) mcg/ml], declining at 3 and 12 months. All infants had normal number of B-cells (n = 17), adequate levels of immunoglobulins (n = 14), and protecting antibody levels to Tetanus, Diphtheria, Hemophilus influenza-B and hepatitis B (n = 17). All had normal CD4+, CD8+ T-cells, and TREC numbers. TCR repertoire was polyclonal in 18/20 and slightly skewed in 2/20 infants. No serious infections requiring hospitalization were recorded.

Conclusion

We found that T-cell and B-cell immunity is fully mature and immune function is normal in infants exposed in utero to anti-TNFα, as in those exposed to azathioprine. Untreated controls and large-scale studies are needed to confirm these results.
The correlation between probiotic use and outcomes of cancer patients treated with immune checkpoint inhibitors
Authors: Zhang Lilong , Jin Qi , Chai Dongqi , Kuang Tianrui , Li Chunlei , Guan Yongjun , Liu Li , Wang Weixing , Deng Wenhong
Published: August 2022

Objective: Immune checkpoint inhibitors (ICIs) have recently demonstrated promising results in improving the prognosis of cancer patients. The goal of this meta-analysis was to determine the impact of probiotic use on the survival of cancer patients treated with ICIs.

Methods: Before 3 March 2022, the eligible literature was searched using PubMed, EMBASE, Cochrane Library, Google Scholar, and Clinical trials.gov databases. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) were the primary endpoints.

Results: A total of 6 studies met the inclusion criteria, and 1,123 patients were included. Meta-analysis showed a trend for probiotic use to prolong PFS (HR: 0.585, 95% CI: 0.328–1.045, p = 0.070) and increase DCR (HR: 1.868, 95% CI: 0.890–3.922, p = 0.099), although it was of borderline statistical significance. We also found that probiotics significantly improved OS (HR: 0.526, 95% CI: 0.341–0.812, p = 0.004) and ORR (OR: 2.831, 95% CI: 1.578–5.076, p < 0.001) in ICI-treated cancer patients. Besides, subgroup analysis showed that non-small cell lung cancer (NSCLC) patients treated with ICIs in combination with probiotics would achieve significantly longer PFS (HR: 0.532, 95% CI: 0.354–0.798, p = 0.002) and OS (HR: 0.528, 95% CI: 0.306–0.912, p = 0.022), as well as higher ORR (OR: 2.552, 95% CI: 1.279–5.091, p = 0.008) and DCR (OR: 2.439, 95% CI: 1.534–3.878, p < 0.001). Sensitivity analysis showed that the above results are stable and reliable. The publication bias test confirmed that there was no publication bias in these results.

Conclusion: Current evidence reveals that probiotics can improve the efficacy of ICI treatment in NSCLC patients.

Systematic Review Registeration:https://www.crd.york.ac.uk/prospero/, identifier CRD42022316104.