Zanubrutinib, Obinutuzumab, and Venetoclax for First-Line Treatment of Mantle Cell Lymphoma with a TP53 Mutation.

BACKGROUND: TP53-mutant mantle cell lymphoma (MCL) is associated with poor survival outcomes with standard chemoimmunotherapy. Dual BTK and BCL2-inhibition with or without anti-CD20 monoclonal antibody therapy has shown promising activity in TP53-mutant MCL. We conducted a multi-center phase 2 study of zanubrutinib, obinutuzumab, and venetoclax (BOVen) in untreated MCL patients with TP53 mutation. Patients initially received zanubrutinib 160mg twice daily and obinutuzumab. Obinutuzumab 1000mg was given on cycle 1 day 1, 8, 15 and day 1 of cycles 2-8. After 2 cycles, venetoclax was added with weekly dose-ramp up to 400mg daily. After 24 cycles, if patients were in complete remission with undetectable minimal residual disease using an immunosequencing assay, treatment was discontinued. The primary endpoint was met if ³11 patients were progression free at 2 years. The study included 25 patients with untreated MCL with TP53 mutation. The best overall response rate was 96% (24/25) and the complete response rate was 88% (22/25). Frequency of uMRD5 and uMRD6 at cycle 13 was 95% (18/19) and 84% (16/19). With median follow up of 28.2 months, the primary endpoint was met with a 2-year progression-free survival of 72%, and the 2-year disease-specific and overall survival were 91% and 76%, respectively. Common side effects were generally low grade and included diarrhea (64%), neutropenia (32%), and infusion-related reactions (24%). BOVen was well tolerated and met its primary efficacy endpoint in TP53-mutant mantle cell lymphoma. These data support its use and further evaluation of the BOVen regimen in this high-risk population. NCT03824483.

Porcine deltacoronavirus nucleocapsid protein antagonizes JAK-STAT signaling pathway by targeting STAT1 through KPNA2 degradation.

Porcine deltacoronavirus (PDCoV) is an enteric pathogenic coronavirus that causes acute and severe watery diarrhea in piglets and has the ability of cross-species transmission, posing a great threat to swine production and public health. The interferon (IFN)-mediated signal transduction represents an important component of virus-host interactions and plays an essential role in regulating viral infection. Previous studies have suggested that multifunctional viral proteins encoded by coronaviruses antagonize the production of IFN via various means. However, the function of these viral proteins in regulating IFN-mediated signaling pathways is largely unknown. In this study, we demonstrated that PDCoV and its encoded nucleocapsid (N) protein antagonize type I IFN-mediated JAK-STAT signaling pathway. We identified that PDCoV infection stimulated but delayed the production of IFN-stimulated genes (ISGs). In addition, PDCoV inhibited JAK-STAT signal transduction by targeting the nuclear translocation of STAT1 and ISGF3 formation. Further evidence showed that PDCoV N is the essential protein involved in the inhibition of type I IFN signaling by targeting STAT1 nuclear translocation via its C-terminal domain. Mechanistically, PDCoV N targets STAT1 by interacting with it and subsequently inhibiting its nuclear translocation. Furthermore, PDCoV N inhibits STAT1 nuclear translocation by specifically targeting KPNA2 degradation through the lysosomal pathway, thereby inhibiting the activation of downstream sensors in the JAK-STAT signaling pathway. Taken together, our results reveal a novel mechanism by which PDCoV N interferes with the host antiviral response.IMPORTANCEPorcine deltacoronavirus (PDCoV) is a novel enteropathogenic coronavirus that receives increased attention and seriously threatens the pig industry and public health. Understanding the underlying mechanism of PDCoV evading the host defense during infection is essential for developing targeted drugs and effective vaccines against PDCoV. This study demonstrated that PDCoV and its encoded nucleocapsid (N) protein antagonize type I interferon signaling by targeting STAT1, which is a crucial signal sensor in the JAK-STAT signaling pathway. Further experiments suggested that PDCoV N-mediated inhibition of the STAT1 nuclear translocation involves the degradation of KPNA2, and the lysosome plays a role in KPNA2 degradation. This study provides new insights into the regulation of PDCoV N in the JAK-STAT signaling pathway and reveals a novel mechanism by which PDCoV evades the host antiviral response. The novel findings may guide us to discover new therapeutic targets and develop live attenuated vaccines for PDCoV infection.

Inhibition of growth of hepatocellular carcinoma by co-delivery of anti-PD-1 antibody and sorafenib using biomimetic nano-platelets.

BACKGROUND: Traditional nanodrug delivery systems have some limitations, such as eliciting immune responses and inaccuracy in targeting tumor microenvironments. MATERIALS AND METHODS: Targeted drugs (Sorafenib, Sora) nanometers (hollow mesoporous silicon, HMSN) were designed, and then coated with platelet membranes to form aPD-1-PLTM-HMSNs@Sora to enhance the precision of drug delivery systems to the tumor microenvironment, so that more effective immunotherapy was achieved. RESULTS: These biomimetic nanoparticles were validated to have the same abilities as platelet membranes (PLTM), including evading the immune system. The successful coating of HMSNs@Sora with PLTM was corroborated by transmission electron microscopy (TEM), western blot and confocal laser microscopy. The affinity of aPD-1-PLTM-HMSNs@Sora to tumor cells was stronger than that of HMSNs@Sora. After drug-loaded particles were intravenously injected into hepatocellular carcinoma model mice, they were demonstrated to not only directly activate toxic T cells, but also increase the triggering release of Sora. The combination of targeted therapy and immunotherapy was found to be of gratifying antineoplastic function on inhibiting primary tumor growth. CONCLUSIONS: The aPD-1-PLTM-HMSNs@Sora nanocarriers that co-delivery of aPD-1 and Sorafenib integrates unique biomimetic properties and excellent targeting performance, and provides a neoteric idea for drug delivery of personalized therapy for primary hepatocellular carcinoma (HCC).

Molecular detection and genetic characteristics of porcine circovirus 3 and porcine circovirus 4 in central China.

Porcine circoviruses (PCVs) are a significant cause of concern for swine health, with four genotypes currently recognized. Two of these, PCV3 and PCV4, have been detected in pigs across all age groups, in both healthy and diseased animals. These viruses have been associated with various clinical manifestations, including porcine dermatitis and nephropathy syndrome (PDNS) and respiratory and enteric signs. In this study, we detected PCV3 and PCV4 in central China between January 2022 and February 2023. We tested fecal swabs and tissue samples from growing-finishing and suckling pigs with or without respiratory and systemic manifestations and found the prevalence of PCV3 to be 15.15% (15/99) and that of PCV3/PCV4 coinfection to be 4.04% (4/99). This relatively low prevalence might be attributed to the fact that most of the clinical samples were collected from pigs exhibiting respiratory signs, with only a few samples having been obtained from pigs with diarrhea. In some cases, PCV2 was also detected, and the coinfection rates of PCV2/3, PCV2/4, and PCV2/3/4 were 6.06% (6/99), 5.05% (5/99), and 3.03% (3/99), respectively. The complete genomic sequences of four PCV3 and two PCV4 isolates were determined. All four of the PCV3 isolates were of subtype PCV3b, and the two PCV4 isolates were of subtype PCV4b. Two mutations (A24V and R27K) were found in antibody recognition domains of PCV3, suggesting that they might be associated with immune escape. This study provides valuable insights into the molecular epidemiology and evolution of PCV3 and PCV4 that will be useful in future investigations of genotyping, immunogenicity, and immune evasion strategies.

Identification of changes in bile composition in pancreaticobiliary reflux based on liquid chromatography/mass spectrometry metabolomics.

INTRODUCTION: Pancreaticobiliary reflux (PBR) can induce gallstone formation; however, its pathogenic mechanism remains unclear. In this study, we explored the mechanism of PBR by the non-targeted metabolomic analysis of bile in patients with PBR. OBJECTIVE: The aim of this study was to investigate the pathogenic mechanism in PBR by the non-targeted metabolomic analysis of bile collected during surgery. METHODS: Sixty patients who underwent gallstone surgery at our center from December 2020 to May 2021 were enrolled in the study. According to the level of bile amylase, 30 patients with increased bile amylase ( > 110 U/L) were classified into the PBR group, and the remaining 30 patients were classified into the control group (≤ 110 U/L). The metabolomic analysis of bile was performed. RESULTS: The orthogonal projections to latent structure-discriminant analysis of liquid chromatography mass spectrometry showed significant differences in bile components between the PBR and control groups, and 40 metabolites were screened by variable importance for the projection value (VIP > 1). The levels of phosphatidylcholine (PC) and PC (20:3(8Z,11Z,14Z)/14:0) decreased significantly, whereas the levels of lysoPC (16:1(9z)/0:0), lysoPC (15:0), lysoPC (16:0), palmitic acid, arachidonic acid, leucine, methionine, L-tyrosine, and phenylalanine increased. CONCLUSIONS: Significant differences in bile metabolites were observed between the PBR and control groups. Changes in amino acids and lipid metabolites may be related to stone formation and mucosal inflammation.

Fluorescence Recognition of Hydrazine Driven by Neighboring Group Participation.

Hydrazine (N2H4) has toxic effects on the environment. Although a variety of reactive probes have been used to identify hydrazine, practical applications required continuous development of hydrazine fluorescent probes with improved performance. Here, we applied the neighboring group participation (NGP) to the design of a fluorescent probe for hydrazine. The probe exhibited a rapid response to N2H4 and strong anti-interference ability, with detection limited to 0.031 µmol/L. Theoretical calculation showed that the energy barrier could be reduced by NGP. The cyclic intermediate formed by the indole ring and the α-ester carbonyl group significantly reduced the activation energy of the reaction. Practically, the probe could detect hydrazine in actual water samples.

Vertical heterogeneity enhances network complexity and stability of co-occurrence microbes in the eastern Indian Ocean.

Microbes are core to driving biogeochemical cycles and differ between sun-drenched surface and relatively dark deep oceans. However, their distinct contributions to the organization and association of communities are still remaining elusive. Here, their assembly and co-occurrence stability are systematically researched along the surface and vertical gradients in the eastern Indian Ocean. The distribution of surface microbes was grouped tightly with closer phylogenetic distance and broader niche breadth, and separately from those vertical samples. Clear distance-decay of community similarity was observed in surface microbes with lower richness, while more diverse microeukaryotes and prokaryotes were observed in surface and vertical environments, respectively. Co-occurrence microbes along vertical gradients had a more complex network that was dominated by prokaryotes, while exhibited a lower modularity compared to the surface network. Microbial associations along vertical gradients were more stable and resilient, with lower robustness, higher vulnerability, and a relatively consistent fragmentation. Moreover, prokaryotes contribute greatly to the network topology and stability compared to microeukaryotes in surface environments, emphasizing their distinct functions and survival strategies in maintaining community stability across spatial variations. Environmental selection and community differentiation led to the divergence in organization and potential function of microbes. This study shed light on new perspectives on how marine microbes were associated with and influenced by spatial heterogeneity and their distinct roles in community organization in the face of environmental fluctuations.

The hsa_circ_0000276-ceRNA regulatory network and immune infiltration in cervical cancer.

BACKGROUND: Our previous studies have confirmed that miR-154-5p can regulate pRb expression, and thus, play a tumor suppressor role in HPV16 E7-induced cervical cancer. However, its upstream molecules have not been elucidated in the progression of cervical cancer. This study aimed to explore the role of the miR-154-5p upstream molecule, hsa_circ_0000276 in cervical cancer development and its possible mechanisms of action. METHODS: We detected differences in whole transcriptome expression profiles of cervical squamous carcinoma and tissues adjacent to cervical cancer tissues from patients using microarray technology to predict circular RNAs (circRNAs) with binding sites to miR-154-5p. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the expression of hsa_circ_0000276 (which had the strongest binding capacity to miR-154 and was selected as the target molecule) in cervical cancer tissues, followed by in vitro functional assays. Downstream microRNAs (miRNAs) and mRNAs of hsa_circ_0000276 were identified using transcriptome microarray data and databases, while the protein-protein interaction networks were obtained using STRING. A competing endogenous RNA (ceRNA) network centered on hsa_circ_0000276 was constructed using Cytoscape and GO and KEGG databases. Abnormal expression and prognosis of critical downstream molecules were analyzed using gene databases and molecular experiments. qRT-PCR and western blot analysis was performed to verify the expression of candidate genes. RESULTS: We identified 4,001 differentially expressed circRNAs between HPV16-positive cervical squamous carcinoma and benign cervical tissues and 760 circRNAs targeting miR-154-5p, including hsa_circ_0000276. hsa_circ_0000276 and miR-154-5p directly bound, and hsa_circ_0000276 was upregulated, in cervical precancerous lesions and cervical cancer tissues and cells. Silencing hsa_circ_0000276 inhibited G1/S transition and cell proliferation and promoted apoptosis in SiHa and CaSki cells. Bioinformatics analysis showed that the hsa_circ_0000276 ceRNA network included 17 miRNAs and seven mRNAs, and downstream molecules of hsa_circ_0000276 were upregulated in cervical cancer tissues. These downstream molecules were associated with a poor prognosis and affected cervical cancer-associated immune infiltration. Of these, expression of CD47, LDHA, PDIA3, and SLC16A1 was downregulated in sh_hsa_circ_0000276 cells. CONCLUSIONS: Our findings show that hsa_circ_0000276 exerts cancer-promoting effects in cervical cancer and is an underlying biomarker for cervical squamous cell carcinoma.

Visible-Light Photocatalytic Aerobic C═C Bond Cleavage of Alkenes to Carbonyls by CsPbBr3 Nanocrystals.

Herein, we reported a facile and readily accessible visible-light-driven photocatalytic protocol to induce oxidative cleavage of C═C bonds to corresponding carbonyls using CsPbBr3 nanocrystals as photocatalysts. This catalytic system was applicable to a wide range of terminal and internal alkenes. Detailed mechanism studies indicated that a single-electron transfer (SET) process was involved in this transformation, wherein the superoxide radical (O2•-) and photogenerated holes played crucial roles. Additionally, DFT calculations revealed that the reaction was initiated by the addition of O2•- to the terminal carbon atom of the C═C bond and completed by releasing one molecular formaldehyde by the formed [2 + 2] intermediate; the latter conversion was a rate-determining process.

Detection and genetic analysis of porcine circovirus-like virus in pigs with diarrhea between 2016 and 2021 in Henan and Shanxi provinces of China.

Porcine circovirus-like virus (PCLV) is a recently discovered virus that may be associated with diarrhea in pigs. To investigate the epidemic profile and genetic characteristics of this virus, 175 clinical samples (141 intestinal samples, 17 blood samples, and 17 fecal samples) were collected from diseased piglets during outbreaks of diarrhea from 33 pig farms in 19 cities of Henan and Shanxi provinces of China between 2016 and 2021 and were screened by PCR for the presence of PCLV. The results showed that the positive rate for PCLV was 32% (56/175) at the sample level, 60.6% (20/33) at the farm level, and 57.9% (11/19) at the city level, which varied from 5.88% to 44.12% between 2016 and 2021. It was also found that PCLV occurred in coinfections with porcine circovirus type 2 (PCV2), PCV3, PCV4, porcine epidemic diarrhea virus, and porcine reproductive and respiratory syndrome virus, but no nucleic acids were detected for transmissible gastroenteritis virus, porcine deltacoronavirus, or porcine rotavirus in piglets with diarrhea. Notably, PCLV was detected in 13 diarrheal piglets from four different farms that were negative for the other porcine viruses. These findings suggest that PCLV may be associated with porcine diarrhea and that it has been circulating in piglets in Henan and Shanxi provinces of China. In addition, the complete genomes of 13 PCLV strains were sequenced and found to share 35.4%-91.0% nucleotide sequence identity with sequences available in the GenBank database. Phylogenetic analysis based on Rep amino acid sequences revealed that the 13 PCLV strains from this study clustered in group 1 and were closely related to eight Chinese PCLV strains, Bo-Circo-like virus CH, American strains 21 and 22, and Hungarian strains 288_4 and 302_4, but they differed genetically from seven other foreign PCLV strains. The whole genome and rep gene of 13 PCLV strains in this study were 72.2%-82% and 83.8%-89.7% identical, respectively, to those of Bo-Circo-like virus strain CH, indicating that PCLV is a novel virus in pigs that may be involved in cross-species transmission. Evidence of a recombination event was found in the rep region of the 13 PCLV strains sequenced. This study enriches the epidemiological data on PCLV infection in pigs in China and lays a foundation for further study on the pathogenesis of PCLV.

Simultaneous detection and phylogenetic analysis of porcine epidemic diarrhea virus and porcine circovirus 4 in Henan province, China.

Porcine circovirus 4 (PCV4) is a recently discovered circovirus that was first reported in 2019 in several pigs in Hunan province of China and has also been identified in pigs infected with porcine epidemic diarrhea virus (PEDV). To further investigate the coinfection and genetic diversity of these two viruses, 65 clinical samples (including feces and intestinal tissues) were collected from diseased piglets on 19 large-scale pig farms in Henan province of China, and a duplex SYBR Green I-based quantitative real-time polymerase chain reaction (qPCR) assay was developed for detecting PEDV and PCV4 simultaneously. The results showed that the limit of detection was 55.2 copies/µL and 44.1 copies/µL for PEDV and PCV4, respectively. The detection rate for PEDV and PCV4 was 40% (26/65) and 38% (25/65), respectively, and the coinfection rate for the two viruses was 34% (22/65). Subsequently, the full-length spike (S) gene of eight PEDV strains and a portion of the genome containing the capsid (Cap) gene of three PCV4 strains were sequenced and analyzed. Phylogenetic analysis showed that all of the PEDV strains from the present study clustered in the G2a subgroup and were closely related to most of the PEDV reference strains from China from 2011 to 2021, but they differed genetically from a vaccine strain (CV777), a Korean strain (virulent DR1), and two Chinese strains (SD-M and LZC). It is noteworthy that two PEDV strains (HEXX-24 and HNXX-24XIA) were identified in one sample, and the HNXX-24XIA strain had a large deletion at amino acids 31-229 of the S protein. Moreover, a recombination event was observed in strain HEXX-24. Phylogenetic analysis based on the amino acid sequence of the PCV4 Cap protein revealed that PCV4 strains were divided into three genotypes: PCV4a1, PCV4a2, and PCV4b. Three strains in the present study belonged to PCV4a1, and they had a high degree of sequence similarity (>98% identity) to other PCV4 reference strains. This study not only provides technical support for field investigation of PEDV and PCV4 coinfection but also provides data for their prevention and control.

Molecular breeding for improvement of photothermal adaptability in soybean.

Soybean (Glycine max (L.) Merr.) is a typical short-day and temperate crop that is sensitive to photoperiod and temperature. Responses of soybean to photothermal conditions determine plant growth and development, which affect its architecture, yield formation, and capacity for geographic adaptation. Flowering time, maturity, and other traits associated with photothermal adaptability are controlled by multiple major-effect and minor-effect genes and genotype-by-environment interactions. Genetic studies have identified at least 11 loci (E1-E4, E6-E11, and J) that participate in photoperiodic regulation of flowering time and maturity in soybean. Molecular cloning and characterization of major-effect flowering genes have clarified the photoperiod-dependent flowering pathway, in which the photoreceptor gene phytochrome A, circadian evening complex (EC) components, central flowering repressor E1, and FLOWERING LOCUS T family genes play key roles in regulation of flowering time, maturity, and adaptability to photothermal conditions. Here, we provide an overview of recent progress in genetic and molecular analysis of traits associated with photothermal adaptability, summarizing advances in molecular breeding practices and tools for improving these traits. Furthermore, we discuss methods for breeding soybean varieties with better adaptability to specific ecological regions, with emphasis on a novel strategy, the Potalaization model, which allows breeding of widely adapted soybean varieties through the use of multiple molecular tools in existing elite widely adapted varieties. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-023-01406-z.

In Vitro Hypoglycemic Diterpenoids from the Roots of Croton yunnanensis.

Fifteen compounds including nine new diterpenes were isolated from the roots of Croton yunnanensis. By HRESIMS, NMR, ECD data, and X-ray diffraction analysis, the new compounds were characterized as eight neo-clerodane diterpenes (compounds 1-8) and one 15,16-dinor-ent-pimarane diterpene (9). All diterpenes were assayed for their hypoglycemic activities. Compounds 1-4, 6, 7, and 10 promoted glucose uptake activity in insulin-resistant 3T3-L1 adipocytes. Compounds 1 and 6 showed insulin sensitizing activity, potentiating conspicuously their glucose uptake activity at a concentration of 20 µM when treated synergistically with low-concentration insulin at 1 nM.

Effects of short-term exposure to simulated microgravity on the physiology of Bacillus subtilis and multiomic analysis.

In our study, Bacillus subtilis was disposed to a simulated microgravity (SMG) environment in high-aspect ratio rotating-wall vessel bioreactors for 14 days, while the control group was disposed to the same bioreactors in a normal gravity (NG) environment for 14 days. The B. subtilis strain exposed to the SMG (labeled BSS) showed an enhanced growth ability, increased biofilm formation ability, increased sensitivity to ampicillin sulbactam and cefotaxime, and some metabolic alterations compared with the B. subtilis strain under NG conditions (labeled BSN) and the original strain of B. subtilis (labeled BSO). The differentially expressed proteins (DEPs) associated with an increased growth rate, such as DNA strand exchange activity, oxidoreductase activity, proton-transporting ATP synthase complex, and biosynthetic process, were significantly upregulated in BSS. The enhanced biofilm formation ability may be related with the DEPs of spore germination and protein processing in BSS, and differentially expressed genes involved in protein localization and peptide secretion were also significantly enriched. The results revealed that SMG may increase the level of related functional proteins by upregulating or downregulating affiliated genes to change physiological characteristics and modulate growth ability, biofilm formation ability (epsB, epsC, epsN), antibiotic sensitivity (penP) and metabolism. Our experiment may gives new ideas for the study of space microbiology.

The effect of head rotation on OSA is associated with disease severity: a cross-sectional study.

PURPOSE: Head rotation is an effective positional therapy for obstructive sleep apnea (OSA). However, not all OSA patients benefit from head rotation. This study aimed to explore the clinical phenotype of OSA patients who can benefit from head rotation. METHODS: We performed a retrospective review of 184 consecutive OSA patients who underwent polysomnography. Head rotation in supine position was determined by high-quality video recording. According to the changes in apnea-hypopnea index (AHI) after head rotation, OSA patients were divided into two groups: patients with response to head rotation(HR) and patients without response to head rotation(NHR). Demographic factors and overnight polysomnography were analyzed. RESULTS: Compared with NHR group, HR group showed significantly lower AHI (51.8 vs 31.5, p < 0.01), time spent with oxygen saturation below 90%(5.3% vs 0.51%, p < 0.01), and higher lowest oxygen saturation(80% vs 86%, p < 0.05). Logistic regression showed that AHI was an independent factor to predict the decrease of AHI in head rotation (OR 0.985, 95% CI 0.970-0.979, p < 0.05). Among mild to moderate group (AHI < 30/h), severe group (30/h ≤ AHI < 60/h), and extremely severe group (AHI ≥ 60/h), the percentage decrease of AHI in head rotation was 18.5%, 9.5%, and 2.6%, respectively. Surprisingly, the percentage decrease of AHI of 6 responders in mild to moderate group was more than 50%. CONCLUSION: OSA patients who respond well to head rotation have less severe disease, and patients with mild to moderate OSA are more likely to improve and benefit from this position. Our research provides potential strategies and insights into the individual treatment of OSA patients.

Efficacy of first-line systemic treatment regimens for recurrent/metastatic head and neck squamous cell carcinoma: a network meta-analysis.

PURPOSE: To evaluate the efficacy on overall survival (OS) and progression-free survival (PFS) of the first-line systemic therapy regimens on 6-, 12-, 18-, 24-, and 30 months in recurrent/metastatic head and neck squamous cell carcinoma (R/M-HNSCC) and figure out the best regimen. METHODS: PubMed, Embase, The Cochrane Library, Scopus, and Google Scholars were systematically searched for studies in regard to the first-line systemic regimens for R/M-HNSCC from inception to March 2022. Odds ratios (ORs) were generated for dichotomous variants by network meta-analysis. The primary endpoint was OS, and the second endpoint was PFS. The software implemented was STATA 17.0 MP. RESULTS: Eventually, 18 studies with 5298 patients and 12 first-line systematic regimens were enrolled. immunotherapy + chemotherapy (OR = 2.30, 95% CI 1.60-3.31) and single immunotherapy (OR = 1.91, 95% CI 1.33-2.76) were significantly superior to the EXTREME on OS at 30th month. Meantime, immunotherapy + chemotherapy (SUCRA = 87.7%) has the highest ranking. TPEx (OR = 1.61, 95% CI 1.05-2.48) showed significantly better efficacy compared with EXTREME on PFS at 12th month. Simultaneously, TPEx (SUCRA = 87.1%) had the highest ranking and was the long-lasting first-echelon regimen both in OS and PFS from a longitudinal perspective. It should be noted that EXTREME included platinum-based chemotherapy + fluorouracil + cetuximab, TPEx included docetaxel + cisplatin + cetuximab. CONCLUSION: Considering the efficacy, safety, compliance, and economic profiles collectively, one of the standard first-line regimens, literally TPEx should be recommended as the best choice for R/M-HNSCC. Furthermore, more head-to-head trials are needed to confirm those findings.

Primary and secondary hyperparathyroidism present different expressions of calcium-sensing receptor.

BACKGROUND: Decreased calcium-sensing receptor (CaSR) has been observed in hyperparathyroidism (HPT) without a known mechanism. The purpose of this study was to evaluate the expression of CaSR in primary (PHPT) and secondary (SHPT) subtypes. METHODS: Immunohistochemical (IHC) staining and quantitative real-time PCR (qRT-PCR) assay were used to measure the differences in expression of CaSR protein and gene in PHPT and SHPT human samples, compared to matched controls. RESULTS: CaSR protein was differentially downregulated in SHPT and PHPT compared to normal parathyroid tissues (2.42 ± 0.5 vs. 3.2 ± 0.62, P < 0.05; 1.8 ± 0.83 vs. 3.2 ± 0.62, P < 0.05, respectively). Furthermore, SHPT tissues exhibited significantly higher levels of CaSR mRNA (0.29 ± 0.23 vs. 0.01 ± 0.12, P < 0.05) and protein (2.42 ± 0.5 vs. 1.8 ± 0.83, P < 0.05) than those in PHPT tissue samples. CONCLUSION: Depressed CaSR expression was a critical pathological hallmark of HPT. We found a differential decline of CaSR, in terms of both mRNA and protein levels, in PHPT and SHPT human samples. We think that CaSR dysregulation occurred at the very beginning of disease onset in PHPT, while a similar pathological scenario appeared at the later stage of SHPT. Future studies should be directed to dissect the mechanistic involvement of CaSR in PHPT and SHPT in order to bring treatment precisions in HPT management.

Susceptibility to mice and potential evolutionary characteristics of porcine deltacoronavirus.

Porcine deltacoronavirus (PDCoV) is a novel coronavirus that causes diarrhea in suckling piglets and has the potential for cross-species transmission, posing a threat to animal and human health. However, the susceptibility profile of different species of mice to PDCoV infection and its evolutionary characteristics are still unclear. In the current study, we found that BALB/c and Kunming mice are susceptible to PDCoV. Our results showed that there were obvious lesions in intestinal and lung tissues from the infected mice. PDCoV RNAs were detected in the lung, kidney, and intestinal tissues from the infected mice of both strains, and there existed wider tissue tropism in the PDCoV-infected BALB/c mice. The RNA and protein levels of aminopeptidase N from mice were relatively high in the kidney and intestinal tissues and obviously increased after PDCoV infection. The viral-specific IgG and neutralizing antibodies against PDCoV were detected in the serum of infected mice. An interesting finding was that two key amino acid mutations, D138H and Q641K, in the S protein were identified in the PDCoV-infected mice. The essential roles of these two mutations for PDCoV-adaptive evolution were confirmed by cryo-electron microscope structure model analysis. The evolutionary characteristics of PDCoV among Deltacoronaviruses (δ-CoVs) were further analyzed. δ-CoVs from multiple mammals are closely related based on the phylogenetic analysis. The codon usage analysis demonstrated that similar codon usage patterns were used by most of the mammalian δ-CoVs at the global codon, synonymous codon, and amino acid usage levels. These results may provide more insights into the evolution, host ranges, and cross-species potential of PDCoV.

Implications of regulator of G-protein signaling 5 expression in the pathogenesis of primary and secondary hyperparathyroidism.

OBJECTIVE: To study the protein and mRNA expressions of regulator of G-protein signaling 5 (RGS5) in the pathogenesis of hyperparathyroidism. METHODS: The expression of RGS5 protein in 20 primary hyperparathyroidism (PHPT), 31 secondary hyperparathyroidism (SHPT), and 20 control cases were studied by immunohistochemistry (IHC). The expression of RGS5 mRNA in 15 PHPT, 102 SHPT, and 7 normal parathyroid tissue were measured by quantitative real-time PCR (qRT-PCR) method. RESULTS: The expressions of RGS5 in PHPT tissues were significantly higher than that in SHPT and normal parathyroid tissues (P < 0.05). While the differences in RGS5 protein expressions between SHPT and respective control samples were not statistically significant (P > 0.05). Likewise, the RGS5 mRNA expression in PHPT was significantly higher than that in SHPT (P < 0.05) and normal parathyroid (P < 0.05) samples. In a similar line, the differences in RGS5 gene expressions between SHPT and control tissues were not statistically significant (P > 0.05). CONCLUSIONS: The characteristic RGS5 protein and mRNA levels in hyperparathyroidism might be helpful in discovering the pathomechanism of hyperparathyroidism and novel therapeutic targets as well.

Epidemiological profile of 338 traumatic spinal cord injury cases in Shandong province, China.

STUDY DESIGN: Hospital-based retrospective review. OBJECTIVE: To describe the epidemiological characteristics of traumatic spinal cord injury (TSCI) in Liaocheng, China. SETTING: Liaocheng People's Hospital. METHODS: Medical records of 338 persons with TSCI admitted to Liaocheng People's Hospital from 2013 to 2017 were reviewed. The detailed information included gender, age, marital status, occupation, time, etiology, level of injury, ASIA grade, spinal stenosis, concomitant injury, treatment, length of stay. RESULTS: Over this period, the mean age (SD) of persons with TSCI was 50.1 (14.1) years, and the male/female ratio was 3.1:1. 96.4% of all were married. The leading cause was fall, followed by motor vehicle accident (MVA). The most common level of injury was the cervical cord. ASIA grade D and A injuries were the most common, accounting for 48.5 and 29.3% respectively. Among the concomitant injuries, spinal fractures were the most common. Within 24 h, 91.1% of individuals with TSCI arrived hospital, 63.3% of all accepted surgery. CONCLUSION: The results showed that fall and MVA were the two main causes, so we should focused on preventing fall and reducing MVA. Cervical spinal stenosis can increase the risk of TSCI, so education should be provided to this population to raise their risk awareness. In addition, timely treatment was critical for TSCI, but the data showed that rescue process was not standard, so it was necessary for medical staff to popularize professional knowledge.