Immunotherapy combined with antiangiogenic therapy as third- or further-line therapy for stage IV non-small cell lung cancer patients with ECOG performance status 2: A retrospective study.

BACKGROUND: Patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 2 probably cannot tolerate chemotherapy or other antitumor therapies. Some studies have reported that immunotherapy combined with antiangiogenic therapy is well-tolerated and shows good antitumor activity. However, the efficacy of this combination as a later-line therapy in patients with ECOG PS 2 is unclear. This study evaluated the effectiveness and safety of this combination strategy as third- or further-line therapy in stage IV non-small cell lung cancer (NSCLC) patients with ECOG PS 2. METHODS: In this retrospective study, patients treated with camrelizumab plus antiangiogenic therapy (bevacizumab, anlotinib, or recombinant human endostatin) were included. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), quality of life (QOL) assessed by ECOG PS, and safety were analyzed. RESULTS: Between January 10, 2019, and February 28, 2024, a total of 59 patients were included. The ORR was 35.6% (21/59) and the DCR was 86.4%. With a median follow-up of 10.5 months (range: 0.7-23.7), the median PFS was 5.5 months (95% confidence interval [CI]: 3.8-7.3) and the median OS was 10.5 months (95% CI: 11.2-13.6). QOL was improved (≥1 reduction in ECOG PS) in 39 patients (66.1%). The most common Grade 3-4 treatment-related adverse events were hepatic dysfunction (6 [10%]), hypertension (5 [8%]), and hypothyroidism (3 [5%]). There were no treatment-related deaths. CONCLUSIONS: Third- or further-line immunotherapy combined with antiangiogenic therapy is well-tolerated and shows good antitumor activity in stage IV NSCLC patients with ECOG PS 2. Future large-scale prospective studies are required to confirm the clinical benefits of this combination therapy.

Monosynaptic restriction of the anterograde herpes simplex virus strain H129 for neural circuit tracing.

Identification of synaptic partners is a fundamental task for systems neuroscience. To date, few reliable techniques exist for whole brain labeling of downstream synaptic partners in a cell-type-dependent and monosynaptic manner. Herein, we describe a novel monosynaptic anterograde tracing system based on the deletion of the gene UL6 from the genome of a cre-dependent version of the anterograde Herpes Simplex Virus 1 strain H129. Given that this knockout blocks viral genome packaging and thus viral spread, we reasoned that co-infection of a HSV H129 ΔUL6 virus with a recombinant adeno-associated virus expressing UL6 in a cre-dependent manner would result in monosynaptic spread from target cre-expressing neuronal populations. Application of this system to five nonreciprocal neural circuits resulted in labeling of neurons in expected projection areas. While some caveats may preclude certain applications, this system provides a reliable method to label postsynaptic partners in a brain-wide fashion.

Reactive Hemophagocytic Lymphohistiocytosis Secondary to Ovarian Adenocarcinoma: A Rare Case Report.

Background: Hemophagocytic lymphohistiocytosis (HLH), a syndrome of immune hyperactivation and abnormal regulation that causes life-threatening inflammation, is mainly characterized by fever, hepatosplenomegaly, cytopenia, and other symptoms. Reactive HLH (rHLH) is typically secondary to immune deregulation caused by underlying rheumatologic, infectious, or malignant conditions. Malignancy-associated HLH (M-HLH) continues to be a critical health problem worldwide. Most malignancies associated with HLH are hematologic tumors, and M-HLH in non-hematologic tumors very rarely occurs. Case Report: A 34-year-old Chinese woman had a history of persistent fever, acute dizziness, and bicytopenia. She was found to have developed bilateral ovarian cancer. Additional tests showed splenomegaly, hemophagocytes in the bone marrow, low natural killer activity, and hyperferritinemia, which met the diagnostic criteria put forth in the Histiocyte Society HLH-2004. The patient was treated with correcting anemia, increased platelets, and glucocorticoid therapy but showed no response. She progressively deteriorated and died 55 days later. Conclusion: Hemophagocytic lymphohistiocytosis related to a solid tumor is extremely rare. To the best of the authors' knowledge, the present case was the first to report rHLH secondary to ovarian adenocarcinoma. It is very significant for a better understanding of the disease mechanisms of HLH and should attract the attention of hematologists and other clinicians as the condition progresses and the cost of treating it increases.

Red wine-inspired tannic acid-KH561 copolymer: its adhesive properties and its application in wound healing.

Damaged tissue with an open wound is one of the daily injuries and can have different levels of severity. Inspired by the textile dyeing, coloration and skin care effect of pyrogallol-rich red wine, tannic acid-KH561 (TA561) copolymer was fabricated by phenol-silanol reaction and polycondensation of silane in an aqueous medium under mild conditions. This copolymer could undergo sol-gel transition via continuous heating or when simply placed at room temperature, during which liquid TA561 oligomers connected with each other to form solid TA561 as a bulk resin or thin film. Combining the advantages of the polyphenols and polysiloxane, TA561 can be used as an adhesive for multiple surfaces, including wood, polytetrafluoroethylene, poly(vinyl chloride), aluminum chips and silicon rubber. Furthermore, TA561 also possessed reducing activity towards Ag+ or Au3+ ions to form the corresponding nanoparticles. An in vivo antimicrobial ability test indicated that TA561 could promote wound healing and showed resistance to methicillin-resistant Staphylococcus aureus (MRSA) infection in comparison with KH561. Indeed, TA561 has the potential to be utilized as a low-cost, green bioadhesive material for skin preparations.

Tumor necrosis factor superfamily 14 is critical for the development of renal fibrosis.

OBJECTIVE: Tumor necrosis factor superfamily protein 14 (TNFSF14) was recently identified as a risk factor in some fibrosis diseases. However, the role of TNFSF14 in renal fibrosis pathogenesis remains unknown. RESULTS: It was found that TNFSF14 levels were significantly increased both in UUO-induced renal fibrotic mice and in patients with fibrotic nephropathy, compared with those in controls. Accordingly, Tnfsf14 deficiency led to a marked reduction in renal fibrosis lesions and inflammatory cytokines expression in the UUO mice. Furthermore, the levels of Sphk1, a critical molecule that causes fibrotic nephropathy, were remarkably reduced in Tnfsf14 KO mice with UUO surgery. In vitro recombinant TNFSF14 administration markedly up-regulated the expression of Sphk1 of primary mouse renal tubular epithelial cells (mTECs). CONCLUSION: TNFSF14 is a novel pro-fibrotic factor of renal fibrosis, for which TNFSF14 up-regulates Sphk1 expression, which may be the underlying mechanism of TNFSF14-mediated renal fibrosis. METHODS: We investigated the effect of TNFSF14 on renal fibrosis and the relationship between TNFSF14 and pro-fibrotic factor sphingosine kinase 1 (Sphk1) by using the unilateral urethral obstruction (UUO)-induced mice renal fibrosis as a model and the specimen of patients with fibrosis nephropathy, by Masson trichrome staining, immunohistochemistry, qRT-PCR, and western blot analysis.

Fibrinogen-like protein 2 deficiency aggravates renal fibrosis by facilitating macrophage polarization.

Renal fibrosis has no effective target for its prevention or reversal. Fibinogen-like protein 2 (Fgl2) is a novel prothrombinase exhibiting coagulation activity and immunomodulatory effects. Although Fgl2 is known to play a vital role in the development of liver and interstitial fibrosis, its function in renal fibrosis remains unclear. In this study, Fgl2 expression was found to be markedly increased in kidney tissues from mice with unilateral ureteral obstruction (UUO)-induced renal fibrosis and patients with chronic kidney disease. However, Fgl2 deficiency aggravated UUO-induced renal fibrosis, as evidenced by the significantly increasing collagen I, fibronectin, and α-SMA expression, extracellular matrix deposition, and profibrotic factor (TGF-ß1) secretion. Administration of rmFgl2 (recombinant mouse Fgl2) significantly alleviated UUO-induced renal fibrosis in mice, suggesting that the increased fibrosis can be reversed by supplementing rmFgl2. Although there was no difference in the percentages of total macrophages between Fgl2+/+ and Fgl2-/- mice, Fgl2 deficiency remarkably facilitated M2 macrophage polarization and accelerated M1 macrophage polarization to a low degree, during UUO-induced renal fibrosis development in mice. Similar results were observed when Fgl2+/+ and Fgl2-/- mice bone marrow-derived macrophages were treated for M1 or M2 polarization. Moreover, Fgl2 deficiency significantly increased the phosphorylation of STAT6, a critical mediator of M2 polarization, in both UUO-induced fibrotic kidney tissues and bone marrow-derived M2 macrophages. In conclusion, the aggravation of renal fibrosis by Fgl2 deficiency is facilitated by the p-STAT6-dependent upregulation of macrophage polarization, especially of M2.

High expression of herpes virus entry mediator is associated with poor prognosis in clear cell renal cell carcinoma.

Herpes virus entry mediator (HVEM), also called tumor necrosis factor receptor superfamily 14 (TNFRSF14), is highly expressed in various tumor tissues and plays critical roles in tumor biology. However, the role of HVEM in clear cell renal cell carcinoma (ccRCC) is unknown. This study evaluated the clinical importance of HVEM in patients with ccRCC. HVEM expression was assessed in fresh and 140 archived paraffin-embedded ccRCC tissue samples by quantitative RT-PCR, western blot, and immunohistochemical staining. HVEM expression was higher in ccRCC than in paired peritumor tissue. Kaplan-Meier analysis showed that high level of HVEM expression was associated with poor overall survival (OS) and disease-free survival (DFS) in patients with ccRCC (both P < 0.001). Multivariate analysis indicated that HVEM overexpression was independently prognostic of survival in ccRCC patients. Two novel nomogram systems were constructed by integrating HVEM expression and other clinical parameters to predict OS (c-index 0.75) and DFS (c-index 0.74) in these patients, with both having better predictive accuracy than traditional TNM (c-index 0.65 for OS and 0.639 for DFS) and Fuhrman (c-index 0.612 for OS and 0.641 for DFS) systems. In addition, HVEM silencing led to an observable reduction in tumor cells growth in vitro and in vivo. Taken together, these findings indicate that high HVEM expression is a novel and independent adverse predictor of clinical outcomes in patients with ccRCC and that HVEM may be a potential therapeutic target.

A Viral Receptor Complementation Strategy to Overcome CAV-2 Tropism for Efficient Retrograde Targeting of Neurons.

Retrogradely transported neurotropic viruses enable genetic access to neurons based on their long-range projections and have become indispensable tools for linking neural connectivity with function. A major limitation of viral techniques is that they rely on cell-type-specific molecules for uptake and transport. Consequently, viruses fail to infect variable subsets of neurons depending on the complement of surface receptors expressed (viral tropism). We report a receptor complementation strategy to overcome this by potentiating neurons for the infection of the virus of interest-in this case, canine adenovirus type-2 (CAV-2). We designed AAV vectors for expressing the coxsackievirus and adenovirus receptor (CAR) throughout candidate projection neurons. CAR expression greatly increased retrograde-labeling rates, which we demonstrate for several long-range projections, including some resistant to other retrograde-labeling techniques. Our results demonstrate a receptor complementation strategy to abrogate endogenous viral tropism and thereby facilitate efficient retrograde targeting for functional analysis of neural circuits.

Preoperative practice of surgical position reduces postoperative pain and discomfort in patients receiving kidney surgeries: a nonrandomized pilot study.

OBJECTIVE: Prolonged maintenance of surgical position often results in postoperative pain and discomfort in patients. The present study aimed to investigate the effect of preoperative practice of surgical position on postoperative pain and general comfort in patients receiving kidney surgeries. METHODS: For this nonrandomized pilot study, 74 patients receiving kidney surgeries were selected using the probability sampling method. Patients from ward 1 were assigned to the practice group (n=35), and those from ward 2 were assigned to the control group (n=39). The practice group were instructed to practice the surgical position for 3 days prior to the surgery. Postoperative pain and comfort were surveyed using two questionnaires for 3 days, respectively. The postoperative pain scores were compared using the Student's t-test. RESULTS: The two groups did not differ significantly in wound pain on postoperative days 1-3 (P > 0.05). However, the practice group showed significantly reduced low back pain and contralateral shoulder pain than the control group for 3 postoperative days (P < 0.05). The physical domain score was significantly higher in the practice group than in the control group (P < 0.01). CONCLUSION: Preoperative practice of surgical position can effectively reduce postoperative low back pain and contralateral shoulder pain in patients receiving kidney surgeries and improve the physical comfort.

Effectiveness of dynamic fixation Coflex treatment for degenerative lumbar spinal stenosis.

The aim of the present study was to examine the curative effect of dynamic fixation Coflex treatment for patients with degenerative lumbar spinal stenosis. In the present study, 78 patients with degenerative lumbar spinal stenosis were recruited and divided equally into the control and observation groups. The control group was treated with traditional decompression fusion and the observation group received dynamic fixation Coflex system. Surgery and hospitalization were shorter in the observation group than in the control group. Intraoperative blood loss and drainage volume after surgery were significantly lower in the observation group compared to the control group. The treatment effective rate for the observation group was significantly higher. Visual analogue scale, Oswestry disability index and Japanese Orthopaedic Association pain and functional scores as well as postoperative vertebral canal area and adjacent segment quantitative scores improved after surgery in the two groups, but the observation group showed greater improvement. The curative effect of dynamic fixation Coflex treatment for degenerative lumbar spinal stenosis demonstrates advantages over traditional surgery, including less trauma and bleeding, pain reduction, improved postoperative rehabilitation, and lower incidence of adjacent segment degeneration.

Effects in cattle of genetic variation within the IGF1R gene on the superovulation performance and pregnancy rates after embryo transfer.

The insulin-like growth factor 1 receptor (IGF1R) is a membrane glycoprotein mediating most biological actions of IGF1 and IGF2, and has an important effect on ovulation, pre-implantation embryo development and pregnancy rate. The objectives of this study were to detect IGF1R gene polymorphisms of cattle and analyze the relationship with superovulation performance and pregnancy rates after embryo transfer (ET), as well as the hormone concentrations at the day of ET. One reported SNP of IGF1R G404T and a novel SNP of IGF1R G399A were analyzed in 170 Chinese Holstein donor cows and 118 Luxi recipients cattle. Statistical analysis revealed that the G404T mutation was associated (p=0.019) with increased ovulation rate and females with this mutation had enhanced performance in producing transferable embryos. For the polymorphic locus G399A, recipients with g.399 GG and g.399 GA genotypes had greater pregnancy rates after ET than that of g.399 AA genotype. Furthermore, the same tendency was observed that the genotype groups with greater pregnancy rates had greater progesterone and lesser estrogen concentrations, but these did not reach statistical significance. Results of the present study showed, for the first time, that the polymorphism in IGF1R is associated with superovulation traits, and indicated that the IGFIR gene can be used as a potential marker for donor selection.

Characterization of nuclear localization signals (NLSs) and function of NLSs and phosphorylation of serine residues in subcellular and subnuclear localization of transformer-2ß (Tra2ß).

The serine/arginine-rich (SR) proteins are one type of major actors in regulation of pre-mRNA splicing. Their functions are closely related to the intracellular spatial organization. The RS domain and phosphorylation status of SR proteins are two critical factors in determining the subcellular distribution. Mammalian Transformer-2ß (Tra2ß) protein, a member of SR proteins, is known to play multiple important roles in development and diseases. In the present study, we characterized the subcellular and subnuclear localization of Tra2ß protein and its related mechanisms. The results demonstrated that in the brain the nuclear and cytoplasmic localization of Tra2ß were correlated with its phosphorylation status. Using deletional mutation analysis, we showed that the nuclear localization of Tra2ß was determined by multiple nuclear localization signals (NLSs) in the RS domains. The point-mutation analysis disclosed that phosphorylation of serine residues in the NLSs inhibited the function of NLS in directing Tra2ß to the nucleus. In addition, we identified at least two nuclear speckle localization signals within the RS1 domain, but not in the RS2 domain. The nuclear speckle localization signals determined the localization of RS1 domain-contained proteins to the nuclear speckle. The function of the signals did not depend on the presence of serine residues. The results provide new insight into the mechanisms by which the subcellular and subnuclear localization of Tra2ß proteins are regulated.

Effects of PGR and ESRα genotypes on the pregnancy rates after embryo transfer in Luxi cattle.

Progesterone receptor (PGR) and estrogen receptor alpha (ESRα), which mediate the biological effects of the steroid hormones progesterone and estrogen, play a central role in the establishment and maintenance of pregnancy. The objectives of this study were to detect bovine PGR and ESRα genes polymorphisms and analyze their relationships with the pregnancy rates after embryo transfer and the hormone concentrations at the day of embryo transfer. One reported SNP of PGR G59752C and a novel SNP of ESRα G75935C were analyzed in 132 recipients of Luxi cattle. For the PGR gene, recipients with g.59752 GG and g.59752 GC genotypes had obviously higher pregnancy rates than g.59752 CC genotype. For the ESRα gene, recipients with g.75935 GC and g.75935 CC genotypes had obviously higher pregnancy rates than g.75935 GG genotype. Furthermore, the same tendency was observed for these two genes that the same genotype groups with high pregnancy rates had high progesterone concentration and low estrogen concentration at the day of embryo transfer. These results showed for the first time that PGR G59752C and ESRα G75935C polymorphisms had obvious effects on the pregnancy rates after embryo transfer, and indicated that PGR G59752C and ESRα G75935C polymorphisms could be potential markers for recipient selection of embryo transfer.

HuD regulates the cpg15 expression via the 3'-UTR and AU-rich element.

The candidate plasticity related gene 15 (cpg15) plays important roles in neural development and plasticity. In the present study, we studied the role of the cpg15 3'-untranslated region (UTR) in regulating the expression of the gene. The results showed that the presence of the 3'-UTR significantly decreases, while loss of a putative AU-rich element (ARE) in the 3'-UTR increases the cpg15 expression, indicating that the 3'-UTR and ARE may be essential for regulation of cpg15 expression. In addition, HuD, a neural-specific RNA binding protein, increased the cpg15 expression, which depends on the presence of the 3'-UTR and ARE. RNA-binding protein immunoprecipitation (RIP) assay demonstrated that HuD forms a complex with cpg15 mRNA in the cells of rat hippocampus. Deletion of HuD domains RRM1 plus RRM2 or Hinge region plus RRM3 attenuates the function of HuD in enhancing the cpg15 expression. The results suggest that HuD regulates the cpg15 expression via the 3'-UTR-mediated mechanism, which requires the presence of the ARE.

[Relationship of ubiquitin-ligases APC/C and SCF complex to cancer].

Ubiquitin ligases are an important component in ubiquitination system, which can recognize substrate proteins specially to promote their degradation. Closely related to the generation and development of many tumors, ubiquitin ligases can regulate the growth, differentiation and apoptosis of cells by influencing protein stability, which makes them a potential new target for tumor molecular therapy. There are many kinds of ubiquitin ligases, mainly including APC/C and SCF complex. This article will introduce the structures and functions of these two kinds of ubiquitin ligases and their roles in the tumor generation and development.

[Preparation of coated iron nanoparticles for reduction of trichloroethylene].

Nanoscale alpha-Fe particles with size of about 80 nm were prepared with a microemulsion-coated method. The results demonstrated that this kind of iron particles could exist stably in the air for 7 d compared with nanoscale iron particles prepared by liquid-phase and microemulsion methods. The removal rate of trichloroethylene with an initial concentration of 10 mg x L(-1) can reach 90% in 700 h. The reduction kinetics was studied under room temperature, neutral, and anaerobic conditions. Experiments show that the reduction process of TCE by nanoscale iron particles conforms to pseudo first order reaction law. The apparent rate constant (k(obs)) is proportional to concentration of nanoscale iron particles. The k(obs), values 6.49 x 10(-40, 6.64 x 10(-4), 7.10 x 10(-4), 7.43 x 10(-4) min(-1), are corresponding to concentrations of 87.5, 175, 262.5, 350 mg x L(-1) respectively. In the reaction, nanoscale iron particles provides electrons and forms an inner film of Fe3O4, on the surface of which an outer film of Fe2O3 is formed together with water. TCE is degraded by electrons. The principal degradation products were ethene and ethane, and smaller amounts of other chlorinated degradation products were also founded.

hnRNP-R regulates the PMA-induced c-fos expression in retinal cells.

This study focused on the function of hnRNP-R in the regulation of c-fos expression. We demonstrated that hnRNP-R accelerated the rise and decline phases of c-fos mRNAs and Fos proteins, allowing PMA to induce an augmented pulse response of c-fos expression. Then, we examined the role of the c-fos-derived AU-rich element (ARE) in hnRNP-R-regulated mRNA degradation. Studies with the ARE-GFP reporter gene showed that hnRNP-R significantly reduced the expression of GFP with an inserted ARE. Moreover, immunoprecipitation-RT-PCR analysis demonstrated that in R28 cells and rat retinal tissues, the c-fos mRNA was co-immunoprecipitated with hnRNP-R. These findings indicate that hnRNP-R regulates the c-fos expression in retinal cells, and that the ARE of c-fos mRNAs contributes to this regulation.