bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk Factors for Unilateral Trigeminal Neuralgia Based on Machine Learning
Authors: Ge Xiuhong , Wang Luoyu , Pan Lei , Ye Haiqi , Zhu Xiaofen , Feng Qi , Ding Zhongxiang
Published: April 2022

Purpose

Neurovascular compression (NVC) is considered as the main factor leading to the classical trigeminal neuralgia (CTN), and a part of idiopathic TN (ITN) may be caused by NVC (ITN-nvc). This study aimed to explore the risk factors for unilateral CTN or ITN-nvc (UC-ITN), which have bilateral NVC, using machine learning (ML).

Methods

A total of 89 patients with UC-ITN were recruited prospectively. According to whether there was NVC on the unaffected side, patients with UC-ITN were divided into two groups. All patients underwent a magnetic resonance imaging (MRI) scan. The bilateral cisternal segment of the trigeminal nerve was manually delineated, which avoided the offending vessel (Ofv), and the features were extracted. Dimensionality reduction, feature selection, model construction, and model evaluation were performed step-by-step.

Results

Four textural features with greater weight were selected in patients with UC-ITN without NVC on the unaffected side. For UC-ITN patients with NVC on the unaffected side, six textural features with greater weight were selected. The textural features (rad_score) showed significant differences between the affected and unaffected sides (p < 0.05). The nomogram model had optimal diagnostic power, and the area under the curve (AUC) in the training and validation cohorts was 0.76 and 0.77, respectively. The Ofv and rad_score were the risk factors for UC-ITN according to nomogram.

Conclusion

Besides NVC, the texture features of trigeminal-nerve cisternal segment and Ofv were also the risk factors for UC-ITN. These findings provided a basis for further exploration of the microscopic etiology of UC-ITN.
Novel Variants of ANO5 in Two Patients With Limb Girdle Muscular Dystrophy: Case Report
Authors: Katz Matthew , Garton Fleur C. , Davis Mark , Henderson Robert D. , McCombe Pamela A.
Published: April 2022

Here we report on two unrelated adult patients presenting with Limb girdle muscular dystrophy who were found to have novel variants in ANO5. Both patients had prominent weakness of their proximal lower limbs with mild weakness of elbow flexion and markedly elevated creatine kinase. Next generation sequencing using a custom-designed neuromuscular panel was performed in both patients. In one patient, 336 genes were targeted for casual variants and in the other patient (using a later panel design), 464 genes were targeted. One patient was homozygous for a novel splice variant [c.294+5G>A; p.(Ala98Ins4*)] in ANO5. Another patient was compound heterozygous for two variants in ANO5; a common frameshift variant [c.191dupA; p.(Asn64fs)] and a novel missense variant [c.952G>C; p.(Ala318Pro)]. These findings support the utility of next generation sequencing in the diagnosis of patients presenting with a Limb girdle muscular dystrophy phenotype and extends the genotypic spectrum of ANO5 disease.
Neurofeedback Training of Alpha Relative Power Improves the Performance of Motor Imagery Brain-Computer Interface
Authors: Zhou Qing , Cheng Ruidong , Yao Lin , Ye Xiangming , Xu Kedi
Published: April 2022

Significant variation in performance in motor imagery (MI) tasks impedes their wide adoption for brain-computer interface (BCI) applications. Previous researchers have found that resting-state alpha-band power is positively correlated with MI-BCI performance. In this study, we designed a neurofeedback training (NFT) protocol based on the up-regulation of the alpha band relative power (RP) to investigate its effect on MI-BCI performance. The principal finding of this study is that alpha NFT could successfully help subjects increase alpha-rhythm power and improve their MI-BCI performance. An individual difference was also found in this study in that subjects who increased alpha power more had a better performance improvement. Additionally, the functional connectivity (FC) of the frontal-parietal (FP) network was found to be enhanced after alpha NFT. However, the enhancement failed to reach a significant level after multiple comparisons correction. These findings contribute to a better understanding of the neurophysiological mechanism of cognitive control through alpha regulation.
Altered Brain Activity in Patients With Comitant Strabismus Detected by Analysis of the Fractional Amplitude of Low-Frequency Fluctuation: A Resting-State Functional MRI Study
Authors: Hu Meng-Yan , Pan Yi-Cong , Zhang Li-Juan , Liang Rong-Bin , Ge Qian-Min , Shu Hui-Ye , Li Qiu-Yu , Pei Chong-Gang , Shao Yi
Published: April 2022

More and more studies showed that strabismus is not simply an ocular disease, but a neuro-ophthalmology disease. To analyze potential changes in brain activity and their relationship to behavioral performance in comitant strabismus patients and healthy controls. Our study recruited 28 patients with comitant strabismus and 28 people with matched weight, age range, and sex ratio as healthy controls. Using resting-state functional magnetic resonance imaging, we evaluated fALFF to compare spontaneous brain activity between comitant strabismus and healthy controls. We did hospital anxiety and depression scale questionnaires for these patients. We found significantly lower fALFF value in comitant strabismus patients compared with controls in the left frontal superior medial gyrus and the right middle cingulum. In the latter region, fALFF was significantly negatively correlated with the hospital anxiety and depression scale, as well as the duration of disease. Receiver operating characteristic curve analysis indicated that the fALFF method has clear potential for the diagnosis of comitant strabismus patients. These results revealed abnormal spontaneous activity in two brain regions of comitant strabismus patients, which may indicate underlying pathologic mechanisms and may help to advance clinical treatment.
Red Nucleus Interleukin-6 Evokes Tactile Allodynia in Male Rats Through Modulating Spinal Pro-inflammatory and Anti-inflammatory Cytokines
Authors: Yang Qing-Qing , Li Hao-Nan , Xia Yu-Tong , Tian Xue , Feng Fan , Yang Jian , Xu Ya-Li , Guo Juan , Li Xiao-Qi , Wang Jun-Yang , Zeng Xiao-Yan
Published: April 2022

Our previous studies have clarified that red nucleus (RN) interleukin (IL)-6 is involved in the maintenance of neuropathic pain and produces a facilitatory effect by activating JAK2/STAT3 and ERK pathways. In this study, we further explored the immune molecular mechanisms of rubral IL-6-mediated descending facilitation at the spinal cord level. IL-6-evoked tactile allodynia was established by injecting recombinant IL-6 into the unilateral RN of naive male rats. Following intrarubral administration of IL-6, obvious tactile allodynia was evoked in the contralateral hindpaw of rats. Meanwhile, the expressions of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), IL-1β, and IL-6 were elevated in the contralateral spinal dorsal horn (L4–L6), blocking spinal TNF-α, IL-1β, or IL-6 with neutralizing antibodies relieved IL-6-evoked tactile allodynia. Conversely, the levels of anti-inflammatory cytokines transforming growth factor-β (TGF-β) and IL-10 were reduced in the contralateral spinal dorsal horn (L4–L6), an intrathecal supplement of exogenous TGF-β, or IL-10 attenuated IL-6-evoked tactile allodynia. Further studies demonstrated that intrarubral pretreatment with JAK2/STAT3 inhibitor AG490 suppressed the elevations of spinal TNF-α, IL-1β, and IL-6 and promoted the expressions of TGF-β and IL-10 in IL-6-evoked tactile allodynia rats. However, intrarubral pretreatment with ERK inhibitor PD98059 only restrained the increase in spinal TNF-α and enhanced the expression of spinal IL-10. These findings imply that rubral IL-6 plays descending facilitation and produces algesic effect through upregulating the expressions of spinal pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 and downregulating the expressions of spinal anti-inflammatory cytokines TGF-β and IL-10 by activating JAK2/STAT3 and/or ERK pathways, which provides potential therapeutic targets for the treatment of pathological pain.
Spinal dI4 Interneuron Differentiation From Human Pluripotent Stem Cells
Authors: Xu Jia , Huang Liang-Jiang , Fang Zhengyu , Luo Hong-Mei , Chen Yun-Qiang , Li Ya-Jie , Gong Chen-Zi , Chen Hong
Published: April 2022

Spinal interneurons (INs) form intricate local networks in the spinal cord and regulate not only the ascending and descending nerve transduction but also the central pattern generator function. They are therefore potential therapeutic targets in spinal cord injury and diseases. In this study, we devised a reproducible protocol to differentiate human pluripotent stem cells (hPSCs) from enriched spinal dI4 inhibitory GABAergic INs. The protocol is designed based on developmental principles and optimized by using small molecules to maximize its reproducibility. The protocol comprises induction of neuroepithelia, patterning of neuroepithelia to dorsal spinal progenitors, expansion of the progenitors in suspension, and finally differentiation into mature neurons. In particular, we employed both morphogen activators and inhibitors to restrict or “squeeze” the progenitor fate during the stage of neural patterning. We use retinoic acid (RA) which ventralizes cells up to the mid-dorsal region, with cyclopamine (CYC), an SHH inhibitor, to antagonize the ventralization effect of RA, yielding highly enriched dI4 progenitors (90% Ptf1a+, 90.7% Ascl1+). The ability to generate enriched spinal dI4 GABAergicINs will likely facilitate the study of human spinal IN development and regenerative therapies for traumatic injuries and diseases of the spinal cord.
Sevoflurane-Induced Apoptosis in the Mouse Cerebral Cortex Follows Similar Characteristics of Physiological Apoptosis
Authors: Wang Qi , Li Yuan , Tan Hong , Wang Yingwei
Published: April 2022

General anesthetics are capable of inducing neuronal apoptosis during the rapid synaptogenesis of immature mammalian brains. In this vulnerable time window, physiological apoptosis also occurs to eliminate excess and inappropriately integrated neurons. We previously showed that physiological and ketamine-induced apoptosis in mouse primary somatosensory cortex (S1) followed similar developmental patterns. However, since sevoflurane is more widely used in pediatric anesthesia, and targets mainly on different receptors, as compared with ketamine, it is important to determine whether sevoflurane-induced apoptosis also follows similar developmental patterns as physiological apoptosis or not. Mice at postnatal days 5 (P5) and P9 were anesthetized with 1.5% sevoflurane for 4 h, and the apoptotic neurons in S1 were quantitated by immunohistochemistry. The results showed that sevoflurane raised the levels of apoptosis in S1 without interfering with the developmental patterns of physiological apoptosis. The cells more vulnerable to both physiological and sevoflurane-induced apoptosis shifted from layer V pyramidal neurons at P5 to layers II–IV GABAergic neurons by P9. The magnitude of both sevoflurane-induced and physiological apoptosis was more attenuated at P9 than P5. To determine whether the Akt-FoxO1-PUMA pathway contributes to the developmental decrease in magnitude of both physiological and sevoflurane-induced apoptosis, Western blot was used to measure the levels of related proteins in S1 of P5 and P9 mice. We observed higher levels of antiapoptotic phosphorylated Akt (p-Akt) and phosphorylated FoxO1 (p-FoxO1), and lower levels of the downstream proapoptotic factor PUMA in control and anesthetized mice at P9 than P5. In addition, the Akt-FoxO1-PUMA pathway may also be responsible for sevoflurane-induced apoptosis. Together, these results suggest that magnitude, lamination pattern and cell-type specificity to sevoflurane-induced apoptosis are age-dependent and follow physiological apoptosis pattern. Moreover, The Akt-FoxO1-PUMA pathway may mediate the developmental decreases in magnitude of both physiological and sevoflurane-induced apoptosis in neonatal mouse S1.
Toward Understanding the Brain Dynamics of Music: Learning and Conscious Performance of Lyrics and Melodies With Variable Rhythms and Beats
Authors: Grossberg Stephen
Published: April 2022

A neural network architecture models how humans learn and consciously perform musical lyrics and melodies with variable rhythms and beats, using brain design principles and mechanisms that evolved earlier than human musical capabilities, and that have explained and predicted many kinds of psychological and neurobiological data. One principle is called factorization of order and rhythm: Working memories store sequential information in a rate-invariant and speaker-invariant way to avoid using excessive memory and to support learning of language, spatial, and motor skills. Stored invariant representations can be flexibly performed in a rate-dependent and speaker-dependent way under volitional control. A canonical working memory design stores linguistic, spatial, motoric, and musical sequences, including sequences with repeated words in lyrics, or repeated pitches in songs. Stored sequences of individual word chunks and pitch chunks are categorized through learning into lyrics chunks and pitches chunks. Pitches chunks respond selectively to stored sequences of individual pitch chunks that categorize harmonics of each pitch, thereby supporting tonal music. Bottom-up and top-down learning between working memory and chunking networks dynamically stabilizes the memory of learned music. Songs are learned by associatively linking sequences of lyrics and pitches chunks. Performance begins when list chunks read word chunk and pitch chunk sequences into working memory. Learning and performance of regular rhythms exploits cortical modulation of beats that are generated in the basal ganglia. Arbitrary performance rhythms are learned by adaptive timing circuits in the cerebellum interacting with prefrontal cortex and basal ganglia. The same network design that controls walking, running, and finger tapping also generates beats and the urge to move with a beat.
Progress in Applicability of Scoring Systems Based on Nutritional and Inflammatory Parameters for Ovarian Cancer
Authors: Mu Juan , Wu Yue , Jiang Chen , Cai Linjuan , Li Dake , Cao Jian
Published: April 2022

Ovarian cancer is a malignancy that seriously endangers women’s health; its case fatality rate ranks first among the gynecological malignancies. The status of nutrition of ovarian cancer patients is related to their prognoses. Thus, it is important to evaluate, monitor, and improve the nutritional status of ovarian cancer patients during their treatment. Currently, there are several tools for examining malnutrition and nutritional assessment, including NRI (nutrition risk index), PG-SGA (patient-generated subjective global assessment), and NRS 2002 (nutritional risk screening 2002). In addition to malnutrition risk examination and related assessment tools, the evaluation of muscle mass, C-reactive protein, lymphocytes, and other inflammation status indicators, such as neutrophils to lymphocytes ratio, lymphocyte-to-monocyte ratio, and C-reactive protein-albumin ratio, is of great importance. The nutritional status of ovarian cancer patients undergoing surgery affects their postoperative complications and survival rates. Accurate evaluation of perioperative nutrition in ovarian cancer patients is crucial in clinical settings. An intelligent nutritional diagnosis can be developed based on the results of its systematic and comprehensive assessment, which would lay a foundation for the implementation of personalized and precise nutritional therapy.
Glutamate Supplementation Improves Growth Performance, Rumen Fermentation, and Serum Metabolites in Heat-Stressed Hu Sheep
Authors: Li Chuan , Zhang Jiantong , Li Yanjiao , Zhao Xianghui , Liang Huan , Li Kairong , Qu Mingren , Qiu Qinghua , Ouyang Kehui
Published: April 2022

This study evaluated the effect of glutamate supplementation on the physiological parameters of heat-stressed Hu sheep. Forty-eight male Hu sheep with an average initial body weight of 17.74 ± 0.17 kg were randomly divided into two groups: The control group (CON) was fed a basal diet and a treatment group (GLU) was fed a basal diet + 3 g/head/day of L-glutamate. There were six replications in each group with four sheep in each replication for a 90 days feeding test. Growth performance, serum biochemistry, and serum hormones were measured during phase 1 (1–30 days), phase 2 (31–60 days), and phase 3 (61–90 days) of the experiment; rumen fermentation characteristics, nutrient digestibility, and slaughter performance were measured at the end of the experimental periods. There were no differences in growth performance, serum biochemical indices, and immune indices between CON and GLU during phases 1 and 2. However, a higher average daily gain (ADG), a lower average daily feed intake (ADFI), and a lower F:G ratio (ADFI/ADG) were observed in GLU during phase 3 (p < 0.05). Serum levels of glutamate, globulin, immunoglobulin A, immunoglobulin G, immunoglobulin M, and growth hormone in GLU were higher than those in CON only on day 90 (p < 0.05). Serum levels of heat shock protein 70, adrenocorticotrophic hormone, corticosterone, triiodothyronine, and tetraiodothyronine in GLU were lower than those in CON on day 90 (p < 0.05). At the end of the experiment, ruminal pH, microbial crude protein, ammonia nitrogen, and isovalerate concentrations in GLU were higher than those in CON (p < 0.05). The apparent digestibility of dry matter, organic matter, and crude protein in GLU was higher than those in CON (p < 0.05). There were no differences in carcass traits and organ indices but spleen weight and spleen index tended to be higher in GLU. In conclusion, dietary glutamate supplementation improved rumen fermentation, increased nutrition digestibility and metabolism, enhanced immunity, and promoted growth performance of heat-stressed Hu sheep. This suggests that a longer period of glutamate supplementation (not less than 60 days) at a level of 3 g/head/day is beneficial to Hu sheep under heat stress.
The Status of Selenium and Zinc in the Urine of Children From Endemic Areas of Kashin-Beck Disease Over Three Consecutive Years
Authors: Kang Xin , Liu Yanli , Gong Yi , Huang Lin , Liu Hongliang , Hu Minhan , Huang Ruitian , Chen Feihong , Chen Sijie , Zhang Feiyu , Ning Yujie , Li Cheng , Zhou Rong , Zhao Hongmou , Wang Xi , Guo Xiong
Published: April 2022

Selenium deficiency is one of the main risk factors for Kashin-Beck disease (KBD). This study aimed to detect the status of selenium and zinc in the urine of children from endemic areas of KBD over three consecutive years and to evaluate whether selenium and zinc levels in children in Shaanxi Province remain normal after stopping selenium supplementation. The samples of urine were collected in consecutive years (2017–2019) to detect selenium content by hydride generation atomic fluorescence spectrometry (HGAFS) and to detect zinc content by atomic absorption spectrophotometry (AAS). Generalized estimation equation (GEE) analysis was integrated to assess the comprehensive nutritional status and dietary structure of children. Data were processed in duplicate and analyzed by SPSS 18.0. This study included 30 X-ray-positive KBD cases and 123 healthy children aged 7–12 years. A total of 424 urine and 137 hair samples were collected over three consecutive years for selenium determination. The mean value of urinary selenium in all subjects was 6.86 μg/l (2017), 8.26 μg/l (2018), and 4.04 μg/l (2019), and the mean value of urinary zinc in all subjects was 0.36 mg/l (2017), 0.39 mg/l (2018), and 0.31 mg/l (2019) for the three consecutive years of 2017–2019. The mean values of urinary selenium were 6.56 and 6.94 μg/l (2017), 8.69 and 8.14 μg/l (2018), and 4.57 and 3.90 μg/l (2019) in the KBD-X and normal groups, respectively; and the mean value of urinary zinc were 0.38 and 0.35 mg/l (2017), 0.41 and 0.39 mg/l (2018), and 0.43 and 0.28 mg/l (2019) in the KBD-X and normal groups, respectively. The mean value of hair selenium in 137 subjects was 275.08 μg/kg and the mean values of hair selenium were 267.48 and 276.61 μg/kg in the KBD-X group and normal group, respectively. The level of selenium/zinc showed a trend of increasing first and then decreasing during the three consecutive years. The level of selenium in all subjects from the endemic areas was lower than normal, which reminds us to monitor the state of KBD constantly and adjust selenium salt supplementation in accordance with the changes in the KBD state.
The Impact of Nutritional Supplementation During Pregnancy on the Incidence of Gestational Diabetes and Glycaemia Control
Authors: Ibrahim Ibrahim , Bashir Mohammed , Singh Parul , Al Khodor Souhaila , Abdullahi Hala
Published: April 2022

The nutritional state before and throughout pregnancy has a critical impact on the women's health and the baby's development and growth. The release of placental hormones during pregnancy induces/ increases maternal insulin resistance and promotes nutrition utilization by the fetus. Gestational Diabetes Mellitus (GDM) is the most common medical complication in pregnancy and is associated with significant maternal and fetal morbidity. Several studies have examined the effect of physical activity, healthy eating, and various food supplements on the risk of developing gestational diabetes (GDM) and related outcomes. Among those, Myo-Inositol supplementation has shown encouraging results in the prevention of GDM. Maternal vitamin D deficiency has been associated with an elevated risk of GDM, and supplementation can improve glucose haemostasis by lowering fasting blood glucose, HbA1c, and serum insulin concentration. Probiotics modulate the gut microbiota leading to an improved glucose and lipid metabolism, which is proposed to reduce the risk of GDM. We aim to review the strength and limitation of the current evidence for using some nutritional supplements either as single agents or in combinations on the risk of developing GDM and on glycaemic control.
Tryptophan Metabolism and COVID-19-Induced Skeletal Muscle Damage: Is ACE2 a Key Regulator?
Authors: Takeshita Hikari , Yamamoto Koichi
Published: April 2022

The severity of coronavirus disease 2019 (COVID-19) is characterized by systemic damage to organs, including skeletal muscle, due to excessive secretion of inflammatory cytokines. Clinical studies have suggested that the kynurenine pathway of tryptophan metabolism is selectively enhanced in patients with severe COVID-19. In addition to acting as a receptor for severe acute respiratory syndrome coronavirus 2, the causative virus of COVID-19, angiotensin converting enzyme 2 (ACE2) contributes to tryptophan absorption and inhibition of the renin-angiotensin system. In this article, we review previous studies to assess the potential for a link between tryptophan metabolism, ACE2, and skeletal muscle damage in patients with COVID-19.
Folate, Vitamin B12, and Homocysteine Levels in Women With Neural Tube Defect-Affected Pregnancy in Addis Ababa, Ethiopia
Authors: Kucha Winner , Seifu Daniel , Tirsit Abenezer , Yigeremu Mahlet , Abebe Markos , Hailu Dawit , Tsehay Dareskedar , Genet Solomon
Published: April 2022

Background

Neural tube defects (NTDs) are prevalent congenital defects associated with pre-pregnancy diet with low levels of maternal folate. They are linked to severe morbidity, disability, and mortality, as well as psychological and economic burdens.

Objective

The goal of this study was to determine the levels of folate, vitamin B12, and homocysteine in the blood of women who had a pregnancy impacted by NTDs.

Subjects and Methods

A hospital-based case–control study was undertaken between September 2019 and August 2020. The study comprised a total of 100 cases and 167 controls. Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of folate, vitamin B12, and homocysteine in the serum.

Results

Only 39% of the cases and 54.5% of control mothers reported periconceptional use of folic acid/multivitamin, which indicated a statistically significant difference (p = 0.014). Logistic regression indicated that periconceptional use of folic acid/multivitamin was associated with NTDs (p = 0.015, OR = 1.873, 95% CI: 1.131–3.101). We found that 57% of the cases and 33.5% of controls, as well as 43% of cases and 20.4% of controls had serum folate and vitamin B12 levels below the cut-off value, respectively. Twenty-seven percent of the cases and 6.6% of controls had hyperhomocysteinemia (HHcy). The median concentrations of folate, vitamin B12, and homocysteine in cases and controls were 4.78 and 8.86 ng/ml; 266.23 and 455 pg/ml; 13.43 and 9.7 μmol/l, respectively. The median concentration of folate (p < 0.001) and vitamin B12 (p < 0.001) were significantly lower in the cases than controls, while the homocysteine concentration (p < 0.001) was significantly lower in the controls than cases. Folate [OR (95% CI) = 1.652 (1.226–2.225; p = 0.001)], vitamin B12 [OR (95% CI) = 1.890 (1.393–2.565; p < 0.001], and homocysteine [OR (95% CI) = 0.191 (0.09–0.405; p < 0.001)] levels were associated with NTDs.

Conclusion

Folate and vitamin B12 are deficient in both cases and control mothers. The lower levels of folate and vitamin B12 with an elevated homocysteine level in NTD-affected pregnancy may be an indication that these biochemical variables were risk factors for NTDs. Folate/multivitamin supplementation and/or food fortification should be promoted.
Efficacy of Sorafenib Combined With Immunotherapy Following Transarterial Chemoembolization for Advanced Hepatocellular Carcinoma: A Propensity Score Analysis
Authors: Qin Jian , Huang Yusheng , Zhou Hanjing , Yi Shouhui
Published: April 2022

Aim

The aim of the study is to compare the efficacy and safety of monotherapy with a sequential immune checkpoint inhibitor (ICI) programmed cell death protein-1 (PD-1) and its combination with multi-target drug sorafenib after transcatheter arterial chemoembolization (TACE) for advanced hepatocellular carcinoma (HCC).

Methods

We conducted a retrospective evaluation of patients with advanced HCC who had received sequential PD-1 sorafenib (duplex group, n = 25) or monotherapy PD-1 alone (PD-1 group, n = 41) after TACE during April 2018–September 2021. Propensity score matching (PSM) was applied to correct the selection bias, and 22 pairs were created. The objective response rate (ORR), duration of the overall response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events were analyzed for both groups.

Results

After PSM, the median PFS (7.63 vs. 2.9 months; p = 0.0335) was significantly longer for the duplex group than for the PD-1 group. The median OS (21.63 vs. 16.43 months; p = 0.103) was longer for the duplex group than for the PD-1 group, albeit without any statistical difference. The CR rate, ORR, DCR, and PFS rates at the first, third, and sixth months were higher for the duplex group than for the PD-1 group, wherein the PFS rate of the third and sixth months were statistically different. The OS rates at the sixth, 12th, and 18th months were better for the duplex group than for the PD-1 group, while the 18th-month OS rate (54.5% vs. 33.9%, p = 0.030) were statistically different between them. The most common adverse events after TACE included liver function injury, leukocytopenia, and thrombocytopenia, albeit without any statistical differences between the groups. Cox regression analysis showed that sorafenib combined immunotherapy after TACE and the achieving of CR or PR during the treatment were independent factors affecting PFS. Moreover, CNLC stage-IIIa, TACE frequency ≤2, and achievement of CR or PR were independent influencing factors of OS.

Conclusions

Sequential PD-1 combined with sorafenib therapy after TACE for advanced HCC treatment is safe and effective, especially for patients with good initial treatment response, to further improve the disease prognosis.
Quality of Life Analysis of HPV-Positive Oropharyngeal Cancer Patients in a Randomized Trial of Reduced-Dose Versus Standard Chemoradiotherapy: 5-Year Follow-Up
Authors: Takahashi Mai , Hwang Michael , Misiukiewicz Krysztof , Gupta Vishal , Miles Brett A. , Bakst Richard , Genden Eric , Selkridge Isaiah , Botzler John , Virani Vruti , Moshier Erin , Bonomi Marcelo R. , Posner Marshall R.
Published: April 2022

Background

Human papillomavirus-positive oropharyngeal carcinoma (HPVOPC) portends a more favorable prognosis compared to environmentally related oropharynx cancer (EROPC). Patients with HPVOPC may be overtreated and endure unnecessary long-term toxicities.

Methods

Patients with untreated locally advanced HPVOPC received induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (TPF) and were randomized to standard chemoradiotherapy (sdCRT) (70 Gy) or reduced-dose chemoradiotherapy (rdCRT) (56 Gy) with weekly carboplatin. Patients were followed for changes in five validated quality of life (QoL) surveys: MD Anderson Dysphagia Inventory and Symptom Inventory for head and neck cancer (MDADI, MDASI-HN), Xerostomia Questionnaire (XQ), and European Organization for Research and Treatment of Cancer Questionnaire (EORTC) with head and neck module (EORTC HN). The secondary endpoints of this study were 5-year progression-free survival (PFS) and overall survival (OS).

Results

Twenty patients were enrolled and randomized to rdCRT (n = 12) or sdCRT (n = 8). Median follow-up was 88 months. At 5 years, difference in QoL changes all favored the rdCRT arm and two QoL scales reached statistical significance (EORTC global health score: 11.49 vs. -23.94, P = 0.014; EORTC symptom scale: -7.76 vs. 15.19, P = 0.015). The 5-year PFS and OS were 87.5% and 83.3% for sdCRT and rdCRT, respectively.

Conclusions

Therefore, rdCRT after TPF in HPVOPC is feasible in accordance with the earlier results of the Quarterback Trial and long-term follow-up. These limited results are more favorable in specific QoL domains compared to those of sdCRT and demonstrate equivalent long-term survival.

Clinical Trial Registration

https://clinicaltrials.gov/ct2/show/NCT01706939, The Quarterback Trial [NCT 01706939].
Epidemiological and Clinical Characteristics of Five Rare Pathological Subtypes of Hepatocellular Carcinoma
Authors: Chen Xiaoyuan , Lu Yiwei , Shi Xiaoli , Han Guoyong , Zhang Long , Ni Chuangye , Zhao Jie , Gao Yun , Wang Xuehao
Published: April 2022

Background

Hepatocellular carcinoma (HCC) is a highly heterogeneous tumor with several rare pathological subtypes and which is still poorly understood. This study aimed to describe the epidemiological and clinical spectrum of five rare HCC subtypes and develop a competing risk nomogram for cancer-specific survival prediction.

Methods

The study cohort was recruited from the Surveillance, Epidemiology, and End Results database. The clinicopathological data of 50,218 patients histologically diagnosed with classic HCC and five rare subtypes (ICD-O-3 Histology Code = 8170/3-8175/3) between 2004 and 2018 were reviewed. The annual percent change (APC) was calculated utilizing Joinpoint regression. The nomogram was developed based on multivariable competing risk survival analyses. Akaike information criterion, Bayesian information criterion, C-index, calibration curve, and area under the receiver operating characteristic curve were obtained to evaluate the prognostic performance. A decision curve analysis was introduced to examine the clinical value of the models.

Results

Despite scirrhous carcinoma, which showed a decreasing trend (APC = -6.8%, P = 0.025), the morbidity of other rare subtypes remained stable from 2004 to 2018. The incidence-based mortality was plateau in all subtypes during the period. Clear cell carcinoma is the most common subtype (n = 551, 1.1%), followed by subtypes of fibrolamellar (n = 241, 0.5%), scirrhous (n = 82, 0.2%), spindle cell (n = 61, 0.1%), and pleomorphic (n = 17, ~0%). The patients with fibrolamellar carcinoma were younger and more likely to have a non-cirrhotic liver and better prognoses. Scirrhous carcinoma shared almost the same macro-clinical characteristics and outcomes as the classic HCC. Clear cell carcinoma tended to occur in the Asia-Pacific elderly male population, and more than half of them were large HCC (Size>5cm). Sarcomatoid (including spindle cell and pleomorphic) carcinoma was associated with a larger tumor size, poorer differentiation, and more dismal prognoses. The pathological subtype, T stage, M stage, surgery, alpha-fetoprotein, and cancer history were confirmed as the independent predictors in patients with rare subtypes. The nomogram showed good calibration, discrimination, and net benefits in clinical practice.

Conclusion

The rare subtypes had unique clinicopathological features and biological behaviors compared with the classic HCC. Our findings could provide a valuable reference for clinicians. The constructed nomogram could predict the prognoses with good performance, which is meaningful to individualized management.
Leukemia Stem Cell Frequency at Diagnosis Correlates With Measurable/Minimal Residual Disease and Impacts Survival in Adult Acute Myeloid Leukemia
Authors: Kamel Azza M. , Elsharkawy Nahla M. , Kandeel Eman Z. , Hanafi Marwa , Samra Mohammed , Osman Randa A.
Published: April 2022

Acute myeloid leukemia (AML) is a heterogenous disease in which the initiation and maintenance of the malignant clone is blamed on a rare population of leukemia stem cells (LSCs). The persistence of such a malignant population is referred to as measurable/minimal residual disease (MRD). Evaluation of MRD is the gold standard for follow-up of therapy and constitutes an independent prognostic parameter. As LSCs are the main contributor to the persistence of MRD, then MRD should correlate with the bulk of LSCs at the individual case level. MRD is measured at defined time points during therapy. However, LSCs can be evaluated at diagnosis, which ensures the advantage of early prediction of high-risk patients and allows for early therapeutic decisions. Using two simple four-color monoclonal antibody combinations (CD38/CD123/CD34/CD45 and CD90/CD133/CD45/CD33) and the prism function of the Coulter Navios flow cytometer, the frequency of LSC subsets was evaluated in 84 newly diagnosed adult AML patients. For each panel, 16 possible combinations were detected. Our results showed that there was extreme variability in the percentage of the LSC fraction between different cases, as well as at the individual case level. For each LSC subset, the median value was used to divide cases into low and high expressors. LSC subsets that showed an impact on overall survival (OS) and disease-free survival (DFS) included CD123+, CD 123+/CD34-, CD34-/CD38+/CD123+, CD34+/CD38-/CD123+, CD133+, and CD133+/CD33-. On multivariate analysis, only CD123 (p ≤ 0.001, SE = 0.266, HR = 2.8, 95% CI = 1.74.7) and CD133+/CD33- (p = 0.017, SE = 0.263, HR = 1.9, 95% CI = 1.1–3.1) retained their significance for OS. Likewise, only CD34+/CD38-/CD123+ (p ≤ 0.001, HR 2.3, SE: 0.499, 95% CI: 2.4–17.4) and CD133 (p = 0.015, HR 2.3, SE 0.34, 95% CI: 1.2–4.4) retained their statistical significance for DFS. The LSC frequency at diagnosis showed a moderate to strong correlation with MRD status at day 14 and day 28. In conclusion, the level of LSCs at diagnosis correlated with MRD status at day 14 and day 28 in AML patients and had a deleterious impact on OS and DFS. It may be used as an early marker for high-risk patients allowing for early therapeutic decisions.
The Status and Prospects of Epigenetics in the Treatment of Lymphoma
Authors: Liu Jiaxin , Li Jia-nan , Wu Hongyu , Liu Panpan
Published: April 2022

The regulation of gene transcription by epigenetic modifications is closely related to many important life processes and is a hot research topic in the post-genomic era. Since the emergence of international epigenetic research in the 1990s, scientists have identified a variety of chromatin-modifying enzymes and recognition factors, and have systematically investigated their three-dimensional structures, substrate specificity, and mechanisms of enzyme activity regulation. Studies of the human tumor genome have revealed the close association of epigenetic factors with various malignancies, and we have focused more on mutations in epigenetically related regulatory enzymes and regulatory recognition factors in lymphomas. A number of studies have shown that epigenetic alterations are indeed widespread in the development and progression of lymphoma and understanding these mechanisms can help guide clinical efforts. In contrast to chemotherapy which induces cytotoxicity, epigenetic therapy has the potential to affect multiple cellular processes simultaneously, by reprogramming cells to achieve a therapeutic effect in lymphoma. Epigenetic monotherapy has shown promising results in previous clinical trials, and several epigenetic agents have been approved for use in the treatment of lymphoma. In addition, epigenetic therapies in combination with chemotherapy and/or immunotherapy have been used in various clinical trials. In this review, we present several important epigenetic modalities of regulation associated with lymphoma, summarize the corresponding epigenetic drugs in lymphoma, and look at the future of epigenetic therapies in lymphoma.
Identification of a Rare Variant of c.1777G>A (p.G593S) in the COL1A1 Gene as the Etiology of Recurrent Osteogenesis Imperfecta by Whole-Exome Sequencing
Authors: Zhuang Jianlong , Chen Chunnuan , Chen Yu'e , Luo Qi , Wang Yuanbai , Jiang Yuying , Zeng Shuhong , Xie Yingjun , Chen Dongmei
Published: April 2022

Background

Osteogenesis imperfecta (OI) is a rare heterogeneous disorder typically featured by fragile bones and susceptibility to fracture. The aim of the present study was to explore the genetic etiology of familial recurrent OI and the genotype–phenotype correlation.

Methods

Karyotyping, chromosomal microarray analysis, and whole-exome sequencing (WES) were performed to determine the genetic etiology of OI in the enrolled family. Western blotting analysis was carried out using the fetal skin tissue for type I collagen production analysis.

Results

At the first pregnancy, a c.1777G>A mutation in the COL1A1 gene was detected in the fetus who exhibited skeletal dysplasia. In this second pregnancy, severe fetal skeletal dysplasia was also presented without significant chromosomal abnormality detected by karyotype and chromosomal microarray analysis in the fetus. Further WES results demonstrated a de novo missense mutation of c.1777G>A (p.G593S) in the fetus, which was classified as a pathogenic variant according to the ACMG guidelines. The recurrent mutation in the two fetuses hinted at the possible existence of gonadal mosaicism in the parents, while no mutation in the COL1A1 gene was identified in the DNA from the father's sperm. In addition, Western blot results demonstrated no reduced type I procollagen production in the affected fetus compared with the age-matched controls.

Conclusions

To the best of our knowledge, this is the first study that identified a rare variant of c.1777G>A in the COL1A1 gene that led to recurrent OI in the Chinese population. Additionally, we believe that this rare variant of c.1777G>A in the COL1A1 gene will lead to OI type II. The results of the present study further verify the application value of WES in identifying fetuses with ultrasound anomalies.
Case Report: Mucolipidosis II and III Alpha/Beta Caused by Pathogenic Variants in the GNPTAB Gene (Mucolipidosis)
Authors: Mao Shao-Jia , Zu Yu-Mei , Dai Yang-Li , Zou Chao-Chun
Published: April 2022

Objective

This study aimed to improve the cognition of mucolipidosis (ML) II and III alpha/beta by analyzing the clinical manifestations of two patients.

Methods

The clinical, biochemical, and molecular data of two clinical cases associated with ML II and III alpha/beta were analyzed and compared with other case reports of ML II and III alpha/beta.

Results

The first patient was a 14-month-old girl who was hospitalized because of abnormal postnatal coarse facial features. The child had no abnormal birth history, but developed multiple abnormalities such as psychomotor retardation, abnormal facial features, bilateral limb muscle hypotonia, and genital abnormalities. The X-ray of the spine revealed multiple bone malformations. Brain magnetic resonance imaging (MRI) showed delayed myelination. Genetic testing showed the presence of two compound heterozygous pathogenic variants (c.1364C>T and c.1284+1G>T) in the GNPTAB gene. The second patient was an 18-month-old boy who was hospitalized for recurrent respiratory tract infections. The patient was a high-risk preterm infant with postnatal psychomotor retardation, language development retardation, intellectual disability, and coarse facial features. X-ray showed multiple bone malformations. Craniocerebral ultrasound showed bilateral ventricle widening. Genetic testing showed the presence of two compound heterozygous pathogenic variants (c.1284+1G>T and c.483delT) in the same gene.

Conclusions

ML II and III alpha/beta are rare autosomal-recessive lysosomal storage diseases that are attributed to GNPTAB variants that cause N-acetylglucosamine-1-phosphotransferase deficiency, finally leading to multiple clinical signs and symptoms. A proper ML II and/or III alpha/beta diagnosis requires a combined analysis of a patient's clinical manifestations, imaging examination, enzymatic analysis, and genetic testing results. Ultimately, genetic counseling is essential for this disease.
Prognostic Nomogram for Early Gastric Cancer After Surgery to Assist Decision-Making for Treatment With Adjuvant Chemotherapy
Authors: Zhang Chao , Zhao Shutao , Wang Xudong
Published: April 2022

Background: Most patients with early gastric cancer (EGC) can achieve a better 5-year survival rate after endoscopic resection or surgery. However, indications for adjuvant chemotherapy (ACT) after surgery have not yet been determined.

Methods: A total of 4,108 patients with EGC diagnosed in 2004–2016 were retrospectively analyzed using the Surveillance, Epidemiology, and End Results (SEER) database. Of these, 3,521 patients received postoperative ACT and 587 patients did not. Propensity score matching was used to balance the two groups’ confounding factors. Kaplan-Meier method was utilized to perform survival analysis. Log-rank test was used to compare the differences between survival curves. Cox proportional-hazards regression model was used to screen independent risk factors and build a nomogram for the non-ACT group. The X-tile software was employed to artificially divide all patients into low-, moderate-, and high-risk groups according to the overall survival score prediction based on the nomogram. A total of 493 patients with EGC diagnosed between 2010 and 2014 in our hospital were included for external validation.

Results: Multivariate analysis found that age, sex, race, marital status, primary site, surgical extent, and metastatic lymph node ratio in the non-ACT group were independent prognostic factors for EGC and were included in the construction of the nomogram. The model C-index was 0.730 (95% confidence interval: 0.677–0.783). The patients were divided into three different risk groups based on the nomogram prediction score. Patients in the low-risk group did not benefit from ACT, while patients in the moderate- and high-risk groups did. External validation also demonstrated that moderate- and high-risk patients benefited from ACT.

Conclusion: The study nomogram can effectively evaluate postoperative prognosis of patients with EGC. Postoperative ACT is therefore recommended for moderate- and high-risk patients, but not for low-risk patients.
PRDM16 Regulating Adipocyte Transformation and Thermogenesis: A Promising Therapeutic Target for Obesity and Diabetes
Authors: Jiang Na , Yang Ming , Han Yachun , Zhao Hao , Sun Lin
Published: April 2022

Given that obesity and diabetes have been major public health concerns and that disease morbidities have been rising continuously, effective treatment for these diseases is urgently needed. Because adipose tissue metabolism is involved in the progression of obesity and diabetes, it might be efficient to target adipocyte metabolic pathways. Positive regulatory domain zinc finger region protein 16 (PRDM16), a transcription factor that is highly expressed in adipocytes, plays a key role in adipose tissue metabolism, such as the browning and thermogenesis of adipocytes, the beigeing of adipocytes, the adipogenic differentiation of myoblasts, and the conversion of visceral adipocytes to subcutaneous adipocytes. Furthermore, clinical and basic studies have shown that the expression of PRDM16 is associated with obesity and diabetes and that PRDM16 signaling participates in the treatment of the two diseases. For example, metformin promotes thermogenesis and alleviates obesity by activating the AMPK/αKG/PRDM16 signaling pathway; rosiglitazone alleviates obesity under the synergistic effect of PRDM16; resveratrol plays an antiobesity role by inducing the expression of PRDM16; liraglupeptide improves insulin resistance by inducing the expression of PRDM16; and mulberry leaves play an anti-inflammatory and antidiabetes role by activating the expression of brown fat cell marker genes (including PRDM16). In this review, we summarize the evidence of PRDM16 involvement in the progression of obesity and diabetes and that PRDM16 may be a promising therapy for obesity and diabetes.
A Supervised ML Applied Classification Model for Brain Tumors MRI
Authors: Yu Zhengyu , He Qinghu , Yang Jichang , Luo Min
Published: April 2022

Brain Tumor originates from abnormal cells, which is developed uncontrollably. Magnetic resonance imaging (MRI) is developed to generate high-quality images and provide extensive medical research information. The machine learning algorithms can improve the diagnostic value of MRI to obtain automation and accurate classification of MRI. In this research, we propose a supervised machine learning applied training and testing model to classify and analyze the features of brain tumors MRI in the performance of accuracy, precision, sensitivity and F1 score. The result presents that more than 95% accuracy is obtained in this model. It can be used to classify features more accurate than other existing methods.
Carroll Symmetry, Dark Energy and Inflation
Authors: de Boer Jan , Hartong Jelle , Obers Niels A. , Sybesma Watse , Vandoren Stefan
Published: April 2022

Carroll symmetry arises from Poincaré symmetry upon taking the limit of vanishing speed of light. We determine the constraints on the energy-momentum tensor implied by Carroll symmetry and show that for energy-momentum tensors of perfect fluid form, these imply an equation of state E+P=0 for energy density plus pressure. Therefore Carroll symmetry might be relevant for dark energy and inflation. In the Carroll limit, the Hubble radius goes to zero and outside it recessional velocities are naturally large compared to the speed of light. The de Sitter group of isometries, after the limit, becomes the conformal group in Euclidean flat space. We also study the Carroll limit of chaotic inflation, and show that the scalar field is naturally driven to have an equation of state with w = − 1. Finally we show that the freeze-out of scalar perturbations in the two point function at horizon crossing is a consequence of Carroll symmetry. To make the paper self-contained, we include a brief pedagogical review of Carroll symmetry, Carroll particles and Carroll field theories that contains some new material as well. In particular we show, using an expansion around speed of light going to zero, that for scalar and Maxwell type theories one can take two different Carroll limits at the level of the action. In the Maxwell case these correspond to the electric and magnetic limit. For point particles we show that there are two types of Carroll particles: those that cannot move in space and particles that cannot stand still.