Role of hydrogen sulfide in dermatological diseases.

Hydrogen sulfide (H2S), together with carbon monoxide (CO) and nitric oxide (NO), is recognized as a vital gasotransmitter. H2S is biosynthesized by enzymatic pathways in the skin and exerts significant physiological effects on a variety of biological processes, such as apoptosis, modulation of inflammation, cellular proliferation, and regulation of vasodilation. As a major health problem, dermatological diseases affect a large proportion of the population every day. It is urgent to design and develop effective drugs to deal with dermatological diseases. Dermatological diseases can arise from a multitude of etiologies, including neoplastic growth, infectious agents, and inflammatory processes. The abnormal metabolism of H2S is associated with many dermatological diseases, such as melanoma, fibrotic diseases, and psoriasis, suggesting its therapeutic potential in the treatment of these diseases. In addition, therapies based on H2S donors that release H2S are being developed to treat some of these conditions. In the review, we discuss recent advances in the function of H2S in normal skin, the role of altering H2S metabolism in dermatological diseases, and the therapeutic potential of diverse H2S donors for the treatment of dermatological diseases.

Efficacy of Combination Therapy (Hydrodilatation and Subdeltoid Bursa Injection With Corticosteroid, Mobilization, and Physical Therapy) vs Physical Therapy Alone for Treating Frozen Shoulder: A Randomized Single-Blind Controlled Trial, Phase I.

OBJECTIVE: To compare the efficacy of combination therapy (hydrodilatation and subdeltoid bursa injection with corticosteroid, mobilization, and physical therapy [PT]) with that of PT alone for treating frozen shoulder. DESIGN: A prospective, 2-arm parallel, single-blinded, randomized controlled trial. SETTING: Rehabilitation clinic of a private academic hospital. PARTICIPANTS: Patients (n=70) with frozen shoulder (freezing stage). INTERVENTIONS: Participants (n=35) in the combination group underwent hydrodilatation and subdeltoid bursa injection with corticosteroid twice, mobilization, and usual-care PT for 8 weeks; participants (n=35) in the PT group received only the usual-care PT for 8 weeks. MAIN OUTCOME MEASURES: The Shoulder Pain and Disability Index (SPADI) was the primary outcome measure. The secondary outcome measures were pain scores on a visual analog scale, range of motion (ROM), the Shoulder Disability Questionnaire (SDQ), quality of life (evaluated using the 36-item Short-Form Health Survey [SF-36]), and self-assessment of the treatment effect. RESULTS: Compared with the PT group, the combination group had significantly better pain (during activity), SPADI, SDQ, active and passive ROM, and self-assessment scores (all P<.001) as well as scores on some parts of the SF-36 (physical function and bodily pain, P<.05). Between-group differences were significant at the 1-, 2-, 4-, and 6-month follow-ups. CONCLUSIONS: A combination of hydrodilatation (with corticosteroid), bursal corticosteroid injection, and joint mobilization with PT was superior to PT alone for treating frozen shoulder, and the effects persisted for at least 6 months.

In vitro transdifferentiated signatures of goat preadipocytes into mammary epithelial cells revealed by DNA methylation and transcriptome profiling.

During mammary development, the transdifferentiation of mammary preadipocytes is one of the important sources for lactating mammary epithelial cells (MECs). However, there is limited knowledge about the mechanisms of dynamic regulation of transcriptome and genome-wide DNA methylation in the preadipocyte transdifferentiation process. Here, to gain more insight into these mechanisms, preadipocytes were isolated from adipose tissues from around the goat mammary gland (GM-preadipocytes). The GM-preadipocytes were cultured on Matrigel in conditioned media made from goat MECs to induce GM-preadipocyte-to-MEC transdifferentiation. The transdifferentiated GM-preadipocytes showed high abundance of keratin 18, which is a marker protein of MECs, and formed mammary acinar-like structures after 8 days of induction. Then, we performed transcriptome and DNA methylome profiling of the GM-preadipocytes and transdifferentiated GM-preadipocytes, respectively, and the differentially expressed genes and differentially methylated genes that play underlying roles in the process of transdifferentiation were obtained. Subsequently, we identified the candidate transcription factors in regulating the GM-preadipocyte-to-MEC transdifferentiation by transcription factor-binding motif enrichment analysis of differentially expressed genes and differentially methylated genes. Meanwhile, the secretory proteome of GM-preadipocytes cultured in conditioned media was also detected. By integrating the transcriptome, DNA methylome, and proteome, three candidate genes, four proteins, and several epigenetic regulatory axes were further identified, which are involved in regulation of the cell cycle, cell polarity establishment, cell adhesion, cell reprogramming, and adipocyte plasticity. These findings provide novel insights into the molecular mechanism of preadipocyte transdifferentiation and mammary development.

TREM2+ macrophages suppress CD8+ T-cell infiltration after transarterial chemoembolisation in hepatocellular carcinoma.

BACKGROUND & AIMS: The immune landscape of hepatocellular carcinoma (HCC) following transarterial chemoembolisation (TACE) remains to be clarified. This study aimed to characterise the immune landscape following TACE and the underlying mechanism of HCC progression. METHODS: Tumour samples from five patients with treatment-naive HCC and five patients who received TACE therapy were collected and subjected to single-cell RNA sequencing. Another 22 paired samples were validated using immunofluorescence staining and flow cytometry. To clarify the underlying mechanisms, in vitro co-culture experiments and two types of TREM2-KO/WT mouse models, namely, an HCC cell orthotopic injection model and a spontaneous HCC model, were used. RESULTS: A reduced number of CD8+ T cells and an increased number of tumour-associated macrophages (TAMs) were observed in the post-TACE microenvironment. TACE therapy reduced the cluster CD8_C4, which was highly enriched with tumour-specific CD8+ T cells of pre-exhausted phenotype. TREM2 was found to be highly expressed in TAMs following TACE, which was associated with a poor prognosis. TREM2+ TAMs secreted less CXCL9 but more galectin-1 than did TREM2- TAMs. Galectin-1 promoted PD-L1 overexpression in vessel endothelial cells, impeding CD8+ T cell recruitment. TREM2 deficiency also increased CD8+ T cell infiltration, which inhibited tumour growth in both in vivo HCC models. More importantly, TREM2 deficiency enhanced the therapeutic effect of anti-PD-L1 blockade. CONCLUSIONS: This study shows that TREM2+ TAMs play an important role in suppressing CD8+ T cells. TREM2 deficiency increased the therapeutic effect of anti-PD-L1 blockade by enhancing antitumour activity of CD8+ T cells. These findings explain the reasons for recurrence and progression after TACE and provide a new target for HCC immunotherapy after TACE. IMPACT AND IMPLICATIONS: Studying the immune landscape in post-TACE HCC is important to uncover the mechanisms of HCC progression. By using scRNA sequencing and functional assays, we discovered that both the number and function of CD8+ T cells are compromised, whereas the number of TREM2+ TAMs is increased in post-TACE HCC, correlating with worse prognosis. Moreover, TREM2 deficiency dramatically increases CD8+ T cell infiltration and augments the therapeutic efficacy of anti-PD-L1 blockade. Mechanistically, TREM2+ TAMs display lower CXCL9 and increased Gal-1 secretion than do TREM2- TAMs, with Gal-1 mediating the overexpression of PD-L1 in vessel endothelial cells. These results suggest that TREM2 could be a novel immunotherapeutic target for patients treated with TACE in HCC. This provides an opportunity to break the plateau of limited therapeutic effect. This study has the value of understanding the tumour microenvironment of post-TACE HCC and thinking a new strategy of immunotherapy in the field of HCC. It is therefore of key impact for physicians, scientists and drug developers in the field of liver cancer and gastrointestinal oncology.

KIFC1 aggravates non-small-cell lung cancer cell proliferation and metastasis via provoking TGF-ß/SMAD signal.

Worldwide, the non-small-cell lung cancers (NSCLC) is considered one of the deadliest cancers. Very early onset of distant metastasis is an important reason for the lower survival rate of NSCLC patients. Kinesin family member C1 (KIFC1) with highly protein levels in various of cancers contributes to the initiation and development of many cancers. KIFC1 has also been suggested as a possible marker of NSCLC. Nevertheless, the effects of KIFC1 on NSCLC metastasis has not been researched. To investigate the role of KIFC1 in NSCLC and related mechanisms. Westernblot and quantitative real-time PCR were conducted to test the levels of KIFC1 in NSCLC cancerous tissues and NSCLC cancerous cell lines. Colony formation assay, CCK-8, transwell assay and wound healing assay was conducted to detect the functions of KIFC1 on proliferation, migration and invasion of NSCLC cell lines. WesternBlot was conducted to test the role of KIFC1in EMT and TGF-ß/SMAD pathway. We discovered that the protein levels of KIFC1 were upregulated in NSCLC cancerous cell lines and cancerous tissues from mankind. KIFC1 was positively related with worse clinical staging and lymphnode metastasis of NSCLC patients in clinical data. Overexpressed KIFC1 aggravated expansion, migration and invasion in NSCLC cells, whereas silencing of KIFC1 had the opposite effect in vitro. Mechanistically, the progression of NSCLC was promoted by KIFC1 through induction of EMT and TGF-ß/SMAD signal. KIFC1 promoted proliferation and metastasis through accommodating TGF-ß/SMAD signal, which is a hint that KIFC1 might offer a prospective therapeutic target for the NSCLC treatment.

Comparison of corticosteroid injection, physiotherapy and combined treatment for patients with chronic subacromial bursitis - A randomised controlled trial.

OBJECTIVE: To investigate whether combination of corticosteroid subdeltoid injections and physiotherapy was more effective than either treatment alone in chronic subacromial bursitis. DESIGN: Prospective, three-arm randomised controlled trial. SETTING: Rehabilitation department of an academic hospital. SUBJECTS: Patients with chronic subacromial bursitis. INTERVENTIONS: Patients were divided into corticosteroid injection (N = 36), physiotherapy (N = 40) and combined (N = 35) groups. Two corticosteroid subdeltoid injections in corticosteroid group, 8-week physical therapy emphasising on therapeutic exercise in physiotherapy group, and combined both treatments in combined group. MAIN OUTCOME MEASURES: The primary outcome measures were pain visual analogue scale and Shoulder Pain and Disability Index at 8 weeks after finishing treatment. The secondary outcome measures were active range of motion, Shoulder Disability Questionnaire, Western Ontario Rotator Cuff Index, patient's evaluation of treatment effect, and symptom recurrence. RESULTS: Group comparison showed significant statistical difference in shoulder flexion (P < 0.003) and patient's evaluation of treatment effect (P < 0.001). The time and group interactions comparison revealed significant statistical differences in pain score (P < 0.024), external rotation (P < 0.044) and patient's evaluation of treatment effect (P < 0.001). The above statistics were in favour of the corticosteroid and combined groups rather than physiotherapy group. The percentage of recurrence was 36.1, 7.5 and 17.1 in the corticosteroid, physiotherapy and combined groups, respectively (P < 0.001). CONCLUSION: Corticosteroid subdeltoid injection, or combined with physiotherapy, was superior to physiotherapy alone, but the recurrence rate was least in the physiotherapy group.

The complete mitochondrial genome of Morishitium polonicum (Trematoda, Cyclocoelidae) and its phylogenetic implications.

Trematodes can adversely impact the health and survival of wild animals. The trematode family Cyclocoelidae, which includes large digenean bird parasites, lacks molecular analysis, and reclassifications have not been supported. This study produced the first fully assembled and annotated mitochondrial genome sequence for the trematode Morishitium polonicum. The whole length of the M. polonicum (GenBank accession number: OP930879) mitogenome is 14083 bp, containing 22 transfer ribonucleic acids (tRNAs), 2 ribosomal RNAs (rRNAs, rrnL and rrnS), and a noncoding control section (D-loop) 13777 to 13854 bp in length. The 12 PCG areas have 3269 codons and a total length of 10053 bp, which makes up 71.38% of the mitochondrial genome's overall sequence. Most (10/12) of the PCGs that code for proteins begin with ATG, while the nad4L and nad1 genes have a GTG start codon. Phylogenetic analysis using the concatenated nucleotide sequences of 12 PCGs, and the ML tree analysis results showed that M. polonicum is more closely related to with Echinostomatidae and Fasciolidae, which indicates that the family Cyclocoelidae is more closely associated with Echinochasmidae. This study provides mtDNA information, and analysis of mitogenomic structure and evolution. Moreover, we aimed to understand the phylogenetic relationships of this fluke.

Genome-wide integrated analysis reveals functions of lncRNA-miRNA-mRNA interactions in Atlantic salmon challenged by Aeromonas salmonicida.

Aeromonas salmonicida (A. salmonicida) is a pathogenic bacterium that causes serious problems in the global Atlantic salmon aquaculture industry. In this study, we comprehensively analyzed the profiles of lncRNAs, miRNAs and mRNAs in gills of Atlantic salmon at high-dose A. salmonicida infection (3.06 × 108 CFU/mL), low-dose A. salmonicida infection (3.06 × 105 CFU/mL), and a PBS (100 µL) control. We identified 65 differentially expressed lncRNAs, 41 miRNAs, and 512 mRNAs between the control group and infection groups. Functional analysis showed that these genes were significantly enriched in the p53 signaling pathway, Wnt signaling pathway, mTOR signaling pathway, JAK-STAT signaling pathway, and Toll-like receptor signaling pathway. In addition, we predicted key genes in immune-related pathways and constructed a lncRNA-miRNA-mRNA network based on whole transcriptomic analysis. We further predicted three lncRNA-miRNA-mRNA axes as potential novel biomarkers in regulating the immune response of Atlantic salmon against A. salmonicida infection.

Ultrasonographic imaging findings of the shoulder in patients with Parkinson disease.

BACKGROUND: Shoulder disorders, including frozen shoulder, bursitis, and rotator cuff lesions, are common musculoskeletal problems in patients with Parkinson disease (PD). Because musculoskeletal ultrasound (US) can clearly image shoulder joints, we aimed to evaluate shoulder joints using US in patients with PD and healthy participants and correlation between US and PD severity. METHODS: This is a prospective case-control study. 50 patients with PD and 50 healthy subjects from the outpatient department were administered US for bilateral shoulders. For data analysis, we chose the more severely affected side in the PD group for matching with the corresponding shoulder in the control group according to age, sex, and body mass index. Pain and disability were measured using the Visual Analogue Scale (VAS) for pain, Shoulder Pain and Disability Index (SPADI), and the Shoulder Disability Questionnaire (SDQ). RESULTS: The PD group had higher VAS pain scores during activity (p = 0.003) and rest (p < 0.001), as well as the SPADI and SDQ scores (p < 0.001). In US findings, biceps long head tendon sheath effusion (p = 0.001), humeral head cortical irregularity (p = 0.012), and abnormality in the supraspinatus tendon (p = 0.003) were significantly greater in the PD group. Intra-group analysis in the PD group demonstrated a significant difference in passive flexion (p = 0.019) and supraspinatus tendinopathy (p = 0.033) on US examination during different disease stages. CONCLUSIONS: Patients with PD had more supraspinatus tendinopathy on US findings than control subjects. The lesion was significantly associated with disease severity. CLINICAL TRIAL NUMBER: NCT02702232.

Comparing Photoactivities of Dissolved Organic Matter Released from Rice Straw-Pyrolyzed Biochar and Composted Rice Straw.

Here, we systematically compared the photoactivity and photobleaching behavior between dissolved black carbon (DBC) from rice straw biochar and leached dissolved organic carbon (LDOC) from rice straw compost using complementary techniques. The Fourier transform-ion cyclotron resonance mass spectrometry (FT-ICR MS) analysis showed that DBC was dominated by polycyclic aromatic (55.1%) and tannin-like molecules (24.1%), while LDOC was dominated by lignin-like (58.9%) and tannin-like molecules (19.7%). Under simulated sunlight conditions, DBC had much higher apparent quantum yields for 3DOM* and 1O2 but much lower apparent quantum yields for •OH than LDOC. After a 168 h irradiation, the total number of LDOC formulas identified by FT-ICR MS decreased by 40.1% with concurrent increases in O/C and H/C ratios and also decreases in double bond equivalence minus oxygen (DBE - O) and average molecular weight identified by gel permeation chromatography. However, despite the large decreases in UVA254 and DOC, the total number of DBC formulas decreased only by 12.0% with nearly unchanged O/C ratio, DBE - O values, molecular weight distribution, and benzenepolycarboxylic aromatic condensation (BACon) index regardless of the decreased percentage of condensed aromatic carbon (ConAC %). Compared with LDOC, the photolysis of DBC was much less oxidative and destructive mainly via breakup of a small portion of the highly condensed aromatic rings, probably accompanied by photodecarboxylation.

Inhibition of RhoA Activity Does Not Rescue Synaptic Development Abnormalities and Long-Term Cognitive Impairment After Sevoflurane Exposure.

General anesthetics interfere with dendritic development and synaptogenesis, resulting in cognitive impairment in the developing animals. RhoA signal pathway plays important roles in dendritic development by regulating cytoskeleton protein such as tubulin and actin. However, it's not clear whether RhoA pathway is involved in inhaled general anesthetics sevoflurane-induced synaptic development abnormalities and long-term cognitive dysfunction. Rats at postnatal day 7 (PND7) were injected intraperitoneally with RhoA pathway inhibitor Y27632 or saline 20 min before exposed to 2.8% sevoflurane for 4 h. The apoptosis-related proteins and RhoA/CRMP2 pathway proteins in the hippocampus were measured 6 h after sevoflurane exposure. Cognitive functions were evaluated by the open field test on PND25 rats and contextual fear conditioning test on PND32-33 rats. The dendritic morphology and density of dendritic spines in the pyramidal neurons of hippocampus were determined by Golgi staining and the synaptic plasticity-related proteins were also measured on PND33 rats. Long term potentiation (LTP) from hippocampal slices was recorded on PND34-37 rats. Sevoflurane induced caspase-3 activation, decreased the ratio of Bcl-2/Bax and increased TUNEL-positive neurons in hippocampus of PND7 rats, which were attenuated by inhibition of RhoA. However, sevoflurane had no significant effects on activity of RhoA/CRMP2 pathway. Sevoflurane disturbed dendritic morphogenesis, reduced the number of dendritic spines, decreased proteins expression of PSD-95, drebrin and synaptophysin, inhibited LTP in hippocampal slices and impaired memory ability in the adolescent rats, while inhibition of RhoA activity did not rescue the changes above induced by sevoflurane. RhoA signal pathway did not participate in sevoflurane-induced dendritic and synaptic development abnormalities and cognitive dysfunction in developing rats.

LncRNA DANCR upregulation induced by TUFT1 promotes malignant progression in triple negative breast cancer via miR-874-3p-SOX2 axis.

Triple negative breast cancer (TNBC) is a subtype of breast cancer with poorest survival outcome and is prone to metastasis. TUFT1 and the long non-coding RNA (lncRNA), DANCR, play vital roles in metastasis and progression of various cancers. However, the correlation between TUFT1 and DANCR in TNBC and their downstream molecular mechanisms are still undetermined. We demonstrated that upregulation of TUFT1 in TNBC was related to a worse survival in TNBC patients. The TNBC cells invasiveness was augmented by TUFT1 in a dose-dependent manner, while inhibiting TUFT1 repressed the invasiveness. Particularly, the expression of TUFT1 was positively correlated with the expression of DANCR in TNBC tissues. In addition, TUFT1 increased DANCR expression, while silencing DANCR ameliorated the invasiveness of TNBC cells induced by TUFT1. As demonstrated, TUFT1 interacted with miR-874-3p. Subsequently, qRT-PCR together with luciferase reporter further demonstrated that DANCR acted as competing endogenous (ceRNA) for miR-874-3p, thereby regulating the de-repression of SOX2 and advancing epithelial-mesenchymal transition (EMT) in TNBC. The present research shows that TUFT1 promotes the malignant development in TNBC via enhancing the expression of DANCR. The upregulation of DANCR may contribute to the progression and tumor invasiveness of TNBC, considering that DANCR functions as a miR-874-3p sponge, thus modulating SOX2 positively. Collectively, the present study explored the molecular mechanism underlying TUFT1 in TNBC, raising a TUFT1-mediated therapy for the treatment of patients with TNBC.

HSP70 gene expression responses to the temperature stress in pufferfish (Takifugu rubripes).

In this study, we isolated and characterized HSP70 cDNA from pufferfish (Takifugu rubripes). The 3053 bp full-length TrHSP70 sequence consisted of a 167 bp 5'-UTR (untranslated region), a 2535 bp open reading frame, and a 351 bp 3'-UTR. BLAST analysis revealed that the TrHSP70 shared high similarity with HSP70 sequences in other species. In our study, we set 3 experimental groups as H1 group (20 °C), H2 group (24 °C), and H3 group (28 °C) for checking the expression level of TrHSP70 in T. rubripes. Tissue-specific gene expression results showed that TrHSP70 had higher expression in the intestines than other tissues of the T. rubripes by RT-qPCR. In the experimental group, we found that the expression of TrHSP70 was upregulated in different tissues in the H3 group. The results show that TrHSP70 is a constitutively expressed gene, which plays an important role in maintaining normal physiological function and coping with stress.

Administration of a recombinant ALDH7A1 (rA7) indicates potential regulation of the metabolite and immunology pathways in Atlantic salmon infected with Aeromonas salmonicida.

The bacterium Aeromonas salmonicida is the pathogen responsible for furunculosis, which is a serious disease of salmonids. This disease has a significant economic impact on the economic benefits of the global salmon farming industry. However, the pathogenesis of this disease in fish is still unknown. Members of the aldehyde dehydrogenase gene (ALDH) superfamily play a key role in the enzyme detoxification of endogenous and exogenous aldehydes. In this study, we obtained a recombinant aldehyde dehydrogenase 7A1 (ALDH7A1) protein to find its functions on Atlantic salmon infected by A. salmonicida. The transcriptional response in the liver of Atlantic salmon (Salmo salar) with differing levels of A. salmonicida infection was analysed and compared in order to reveal mechanisms by which ALDH7A1 may confer infection resistance. With the addition of ALDH7A1 protein, it was found that a total of 13,369 genes were annotated with one or more KEGG and localized to 360 KEGG pathways in the high concentration infection group. The differential expression genes were more enriched in immune signalling pathways such as the Toll-like receptor signalling pathway, NF-kappa B signalling pathway and TNF signalling pathway. On the other hand, at low concentrations of infection, KEGG enriched a smaller number of differential expression genes. However, these differential genes were more concentrated in immune signalling pathways such as the PI3K-Akt signalling pathway, JAK-STAT signalling pathway and complement and coagulation cascades. In addition, several known immune-related genes including HSP90α, HSP70, DNA damage-inducible transcript 4, integrin alpha 5 and microtubule-associated protein 2 were among the differentially expressed transcripts. These data provide the first insights into the host-ALDH7A1 vaccine interactome. The results of this study contribute to identifying the potential resistance mechanisms of Atlantic salmon to A. salmonicida infection and determining future treatment strategies.

Transcriptome analysis in Takifugu rubripes and Dicentrarchus labrax gills during Cryptocaryon irritans infection.

Takifugu rubripes and Dicentrarchus labrax are important commercial fish in China that are under serious threat from Cryptocaryon irritans. C. irritans is a ciliated obligate parasite that causes marine white spot disease and leads to heavy economic losses. We analysed the transcriptome in the gills of T. rubripes and D. labrax to compare differentially expressed genes (DEGs) and pathways during infection with C. irritans. In total, we identified 6,901 and 35,736 DEGs from T. rubripes and D. labrax, respectively. All DEGs were annotated into GO terms; 6,901 DEGs from T. rubripes were assigned into 991 sub-categories, and 35,736 DEGs from D. labrax were assigned into 8,517 sub-categories. We mapped DEGs to the KEGG database and obtained 153 and 350 KEGG signalling pathways from T. rubripes and D. labrax, respectively. Immune-related categories included Toll-like receptors, MAPK, lysosome, C-type lectin receptor and NOD-like receptor signalling pathways were significantly enriched pathways. In immune-related signalling pathways, we found that AP-1, P38, IL-1ß, HSP90 and PLA were significantly up-regulated DEGs in T. rubripes, but P38 and PLA were significantly down-regulated in D. labrax. In this study, transcriptome was used to analyse the difference between scaly and non-scaly fish infection by C. irritans, which not only provided a theoretical basis for the infection mechanism of C. irritans, but also laid a foundation for effectively inhibiting the occurrence of this disease. Our work provides further insight into the immune response of host resistance to C. irritans.

Efficacy and safety of cinepazide maleate injection in patients with acute ischemic stroke: a multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Ischemic stroke is a leading cause of morbidity and mortality. Thrombolytic therapy improves disability and survival rates; however, to be effective, it must be given within 4.5 h of onset. Moreover, thrombolytic therapy is frequently contraindicated. Therefore, alternative therapeutic options are required. In China, cinepazide maleate injection has been shown to improve the cerebral collateral circulation and further reduce disability in stroke patients; however, very few studies investigating this therapy have been conducted to date. Therefore, this study aimed to further confirm the efficacy and safety of cinepazide maleate injection in patients with acute ischemic stroke. METHODS: Patients with acute ischemic stroke were administered an intravenous infusion of 320 mg cinepazide maleate or placebo once daily for 14 days. All patients were also administered basic therapy (citicoline sodium). The primary efficacy endpoint was the proportion of patients with a modified Rankin scale (mRS) ≤2 on day 90. Secondary efficacy endpoints included Barthel Index ≥95. Safety was evaluated by recording all adverse events (AEs), monitoring laboratory parameters and vital signs, and electrocardiogram. RESULTS: In total, 937 patients with an acute ischemic stroke were included, with a mean (standard deviation, SD) National Institutes of Health Stroke Scale score of 8.8 (2.4) and a mean (SD) stroke onset of 30.9 (11.4) hours prior. Following treatment for 90 days, the proportion of patients with an mRS score ≤ 2 was significantly higher in the cinepazide maleate group than in the control group (60.9% vs. 50.1%; p = 0.0004). Moreover, the proportion of patients with a Barthel Index of ≥95 on day 90 was also significantly higher in the cinepazide maleate group than in the control group (53.4% vs. 46.7%; p = 0.0230). There were no statistically significant differences in safety parameters between the cinepazide maleate and control groups. CONCLUSIONS: The results of this study show that cinepazide maleate injection is superior to placebo in improving neurological function and activities of daily living, reducing disability, and promoting functional recovery in patients with acute ischemic stroke. Cinepazide maleate injection was safe and well tolerated with no unexpected AEs reported. TRIAL REGISTRATION: Chinese Clinical Trial Registry CTR20160292 and ChiCTR1900023827 . Retrospectively registered June 13, 2019.

Comparison of the effect of Western-made unloading knee brace with physical therapy in Asian patients with medial compartment knee osteoarthritis-A preliminary report.

PURPOSE: To compare the effect of unloading knee brace with physical therapy (PT) in Asian patients with osteoarthritis (OA) of the knee. METHOD: This is a non-random, two-group comparative study. Patients with medial compartment knee OA (n = 41) were assigned to either the brace group (n = 20) or PT group (n = 21). Patients in the brace group were fitted with an unloading knee brace for three months and the PT group received a 60-min session of physiotherapy over the affected knee, three times a week, for three months. The primary outcome measures were the pain visual analogue scale (VAS) and the Western Ontario McMaster University Osteoarthritis Index (WOMAC); the second outcome measures were the 36-item Short-Form Health Survey (SF-36) and patient's satisfaction. The patients were evaluated at baseline, and at one month and three months. RESULTS: Group comparison showed no significant difference regarding pain VAS, WOMAC, SF-36, and patient's satisfaction, except stiffness in WOMAC (P = .006) and social functioning in SF-36 (P = .007). Time and group interaction revealed significant differences only in general health (P = .007) and mental health (P = .006) of SF-36. Within-group comparison found that pain VAS and WOMAC decreased significantly at one months and three months in both groups. CONCLUSION: The effect of brace fitting in patients with knee OA was similar to that of physical therapy. A Western-made unloading knee brace is acceptable in some Asian people with knee OA. CLINICAL TRIAL REGISTRATION NUMBER: NCT02712710.

Programmed Cell Death 1 (PD-1) Inhibitors in Renal Transplant Patients with Advanced Cancer: A Double-Edged Sword?

Given advancements in cancer immunity, cancer treatment has gained breakthrough developments. Immune checkpoint inhibitors, such as programmed cell death 1 (PD-1) inhibitors, are the most promising drugs in the field and have been approved to treat various types of cancer, such as metastatic melanoma, head and neck squamous cell carcinoma, and urothelial carcinoma. However, whether PD-1 inhibitors should be administered to renal transplant patients with advanced cancer remains unclear because the T-cells produced after administration of these inhibitors act against not only tumor antigens but also donor alloantigens. Thus, the use of PD-1 inhibitors in kidney-transplanted patients with advanced cancer is limited on account of the high risk of graft failure due to acute rejection. Hence, finding optimal treatment regimens to enhance the tumor-specific T-cell response and decrease T-cell-mediated alloreactivity after administration of a PD-1 inhibitor is necessary. Thus far, no recommendations for the use of PD-1 inhibitors to treat cancer in renal transplant patients are yet available, and very few cases reporting kidney-transplanted patients treated with PD-1 inhibitors are available in the literature. Therefore, in this work, we review the published cases and suggest feasible approaches for renal transplant patients with advanced malignancy treated by a PD-1 inhibitor. Of the 22 cases we obtained, four patients maintained intact grafts without tumor progression after treatment with a PD-1 inhibitor. Among these patients, one maintained steroid dose before initiation of anti-PD1, two received immunosuppressive regimens with low-dose steroid and calcineurin inhibitor (CNI)-elimination with sirolimus before initiation of anti-PD-1 therapy, and one received combined anti-PD-1, anti-vascular endothelial growth factor (VEGF), and chemotherapy with unchanged immunosuppressive regimens. mammalian target of rapamycin (mTOR) inhibitors and anti-VEGF may act as regulators of tumor-specific and allogenic T-cells. However, more studies are necessary to explore the optimal therapy and ensure the safety and efficacy of PD-1 inhibitors in kidney-transplanted patients.

Efficacy of vortioxetine combined cognitive behaviour intervention therapy on brain-derived neurotrophic factor level on depressive patients.

BACKGROUND: To evaluate the effect of vortioxetine combined with cognitive behaviour intervention on the level of brain-derived neurotrophic factor (BDNF) in the serum of patients with depression and its therapeutic effect. METHODS: A total of 82 depressive patients treated at the School of Basic Medicine, Heilongjiang University of Chinese Medicine from January 2017 to June 2017 were randomised into a control group (n = 41) and intervention group (n = 41) according to a random number table. Both groups were given vortioxetine treatment, while the intervention group adopted an additional cognitive-behavioural therapy at the same time. The therapeutic effect was evaluated using the Hamilton Depression Scale (HAMD). The cognitive function was evaluated using continuous performance test (CPT) and Wisconsin card sorting test (WCST). The changes of BDNF level were detected with the use of enzyme-linked immunosorbent assay. RESULTS: The HAMD score of the intervention group was obviously lower than that of the control group after treatment (P < 0.001). WCST test showed that the number of trials, perseverative errors and non-perseverative errors in the intervention group were significantly lower than those in the control group, while the correct matching number and the number of categories achieved were significantly higher than those in the control group (all P < 0.001). Results of CPT showed that the correct number of responses to stimulus, the verbal fluency and the fluency of classification in the intervention group were significantly higher than those in the control group (all P < 0.05). Moreover, after treatment, the serum BDNF level of the intervention group was significantly higher than that in the control group (P < 0.001). CONCLUSIONS: Vortioxetine combined with cognitive behavioural therapy has a good clinical effect and can largely improve the cognitive function of depressive patients.

Overexpression of geranylgeranyl diphosphate synthase contributes to tumour metastasis and correlates with poor prognosis of lung adenocarcinoma.

This study aimed to evaluate the biological role of geranylgeranyl diphosphate synthase (GGPPS) in the progression of lung adenocarcinoma. GGPPS expression was detected in lung adenocarcinoma tissues by qRT-PCR, tissue microarray (TMA) and western blotting. The relationships between GGPPS expression and the clinicopathological characteristics and prognosis of lung adenocarcinoma patients were assessed. GGPPS was down-regulated in SPCA-1, PC9 and A549 cells using siRNA and up-regulated in A549 cells using an adenoviral vector. The biological roles of GGPPS in cell proliferation, apoptosis, migration and invasion were determined by MTT and colony formation assays, flow cytometry, and transwell and wound-healing assays, respectively. In addition, the regulatory roles of GGPPS on the expression of several epithelial-mesenchymal transition (EMT) markers were determined. Furthermore, the Rac1/Cdc42 prenylation was detected after knockdown of GGPPS in SPCA-1 and PC9 cells. GGPPS expression was significantly increased in lung adenocarcinoma tissues compared to that in adjacent normal tissues. Overexpression of GGPPS was correlated with large tumours, high TNM stage, lymph node metastasis and poor prognosis in patients. Knockdown of GGPPS inhibited the migration and invasion of lung adenocarcinoma cells, but did not affect cell proliferation and apoptosis. Meanwhile, GGPPS inhibition significantly increased the expression of E-cadherin and reduced the expression of N-cadherin and vimentin in lung adenocarcinoma cells. In addition, the Rac1/Cdc42 geranylgeranylation was reduced by GGPPS knockdown. Overexpression of GGPPS correlates with poor prognosis of lung adenocarcinoma and contributes to metastasis through regulating EMT.