Exploring novel systemic therapies for pancreatic cancer: a review of emerging anti-PD-1/PD-L1 combination therapy.

Despite attempts to apply single therapy such as surgical treatment, chemotherapy, or radiotherapy, pancreatic cancer (PC) is still one of the most lethal solid tumors. Moreover, immune checkpoint inhibitors against PD-1/PD-L1, which have shown good efficacies against many other solid tumors, have not shown encouraging results in PC treatment. Therefore, some studies are evaluating the efficacies of combination therapies based on anti-PD-1/PD-L1 for PC. In this review, we summarized the emerging anti-PD-1/PD-L1 combination therapies for PC in these years. We realized that anti-PD-1/PD-L1-based combination therapies have the potential to be efficacious in PC treatment, and further relevant studies are needed. Moreover, we elucidated the reasons for the ineffectiveness of anti-PD-1/PD-L1 alone in PC treatment. We concluded that this was mainly because PC has an immunosuppressive tumor microenvironment and develops drug resistance during treatment. Anti-PD-1/PD-L1-based combination therapeutic regimens that alter the immunosuppressive tumor microenvironment and reduce the development of drug resistance in PC are summarized in this review, and we expect that these regimens will achieve good clinical application prospects.

Autoimmune-mediated secondary-parkinsonism presented with micrographia and cognitive impairment.

Parkinson's disease is a neurodegenerative disorder while secondary-parkinsonism can be caused by infectious, inflammatory, traumatic, vascular, hereditary, paraneoplastic, or even induced by drug/metal poisoning. Here we report an uncommon subacute parkinsonism who presented with micrographia and mild cognitive impairment. The CSF examination showed inflammatory profile and positive anti-NMDAR antibody. The patient showed no improvement with levodopa/benserazide administration but satisfactory response to immunotherapy with methylprednisolone. This case indicated that autoimmune etiology should also be considered in parkinsonism to exclude a treatable condition.

Study on Multifunctional Composite Nanomaterials for Controlled Drug Release in Biomedicine.

Nanoscience is a highly comprehensive, interdisciplinary discipline based on many advanced science and technology, and has developed very rapidly in the past few decades. Nanoscience and technology has been widely used in many fields such as biomedicine, materials science, chemistry, physics, and electronic information engineering. Nanomaterials are widely used due to their many excellent properties such as quantum size effects, small size effects, surface effects, and tunneling effects, and have become hot research areas. It is very suitable as a carrier for antitumor drug molecules, which is conducive to improving drug efficacy and reducing drugs side effects. After selective functionalization, it is highly possible to achieve the loading and release of multiple drug molecules. Based on the magnetic mesoporous Fe3O4-MSNs composite nanoparticles, we have modified a series of organosilane coupling agents on its surface. The most commonly used antitumor drug (adriamycin) in clinical was selected as a model to evaluate the loading and release behavior of modified composite nanoparticles Fe3O4-MSNs on this drug. The results indicate that Fe3O4 is selectively modified after appropriate modification of the silane coupling agent. MSNs carrier can effectively regulate the adsorption and release rate of hydrophilic DOX and hydrophobic PTX, and shows a good drug control ability.

The emerging role of circulating tumor cells in cancer management.

Circulating tumor cells (CTCs) are cells that are shed from the primary tumor and circulate in the blood, and their metastasis and formation of a secondary tumor are closely associated with cancer-related death. Therefore, regulating tumor metastasis through CTCs can be a novel strategy to fight cancer. It has been demonstrated that CTCs can reflect the profile of the primary tumor and provide valuable information about intratumoral heterogeneity and their evolution over time. Moreover, the revelation of the relationship between metastasis and CTCs suggests that CTC regulation represents a promising novel anticancer strategy. Above all, at the molecular level, genetic analysis might be vital in the new era of gene-targeted cancer therapies and contribute to personalized anti-metastasis tumor treatments. In this review, we will focus on the biological significance of CTCs in the peripheral blood and discuss their potential clinical implications in cancer management.

[Laparoscopic selective varicocelectomy versus microscopy-assisted low ligation of the spermatic vein in the treatment of varicocele].

OBJECTIVE: To compare the effects and adverse events of laparoscopic selective varicocelectomy (LV) and microscopy-assisted low ligation of the spermatic vein (MV) in the treatment of varicocele. METHODS: We retrospectively analyzed the clinical data on 310 cases of varicocele treated in our hospital from January 2011 to March 2016, 162 (64 with infertility) by LV with preservation of the testis artery and lymph vessel and the other 148 (69 with infertility) by MV. We followed up the patients for 12 months and made comparisons between the two groups in the operation time, hospital stay, hospital costs, recurrence rate, incidence of complications, and semen quality before and at 3 and 6 months after surgery, and spontaneous pregnancy rate at 12 months postoperatively. RESULTS: The bilateral operation time was markedly shorter in the LV than in the MV group (ï¼»60 ± 16ï¼½ vs ï¼»92 ± 23ï¼½ min, P < 0.05), but no statistically significant differences were found between the two groups in the unilateral operation time (ï¼»38 ± 7ï¼½ vs ï¼»45 ± 10ï¼½ min, P >0.05), hospital stay (ï¼»3.2 ± 0.7ï¼½ vs ï¼»3.5 ± 0.9ï¼½ d, P > 0.05), hospital costs (ï¼»14 862.7 ± 813.2ï¼½ vs ï¼»13 907.3 ± 729.2ï¼½ RMB ¥, P > 0.05), or spontaneous pregnancy rate at 12 months after surgery (35.9% vs 39.1%, P > 0.05). Compared with the baseline, significant improvement was observed in both the LV and MV groups in sperm concentration and the percentage of grade a + b sperm at 6 months postoperatively (P < 0.05), but not at 3 months (P > 0.05). The rate of recurrence was remarkably higher in the LV than in the MV group (7.4% vs 1.4%, P < 0.05) but there were no statistically significant differences between the two groups in the incidence rates of postoperative orchialgia (1.8% vs 0.7%, P > 0.05) and epididymitis (1.2% vs 0, P > 0.05). CONCLUSIONS: For the treatment of varicocele, laparoscopic selective varicocelectomy is comparable to microscopy-assisted low ligation of the spermatic vein in the clinical effect. The former, however, has a significantly higher rate of recurrence than the latter.

Brain injury in combination with tacrolimus promotes the regeneration of injured peripheral nerves.

Both brain injury and tacrolimus have been reported to promote the regeneration of injured peripheral nerves. In this study, before transection of rat sciatic nerve, moderate brain contusion was (or was not) induced. After sciatic nerve injury, tacrolimus, an immunosuppressant, was (or was not) intraperitoneally administered. At 4, 8 and 12 weeks after surgery, Masson's trichrome, hematoxylin-eosin, and toluidine blue staining results revealed that brain injury or tacrolimus alone or their combination alleviated gastrocnemius muscle atrophy and sciatic nerve fiber impairment on the experimental side, simultaneously improved sciatic nerve function, and increased gastrocnemius muscle wet weight on the experimental side. At 8 and 12 weeks after surgery, brain injury induction and/or tacrolimus treatment increased action potential amplitude in the sciatic nerve trunk. Horseradish peroxidase retrograde tracing revealed that the number of horseradish peroxidase-positive neurons in the anterior horn of the spinal cord was greatly increased. Brain injury in combination with tacrolimus exhibited better effects on repair of injured peripheral nerves than brain injury or tacrolimus alone. This result suggests that brain injury in combination with tacrolimus promotes repair of peripheral nerve injury.

Epigallocatechin­3­gallate inhibits the invasion of salivary adenoid cystic carcinoma cells by reversing the hypermethylation status of the RECK gene.

Epigallocatechin­3­gallate (EGCG) is an active and major constituent of green tea. As a non­nucleoside inhibitor of DNA methylation, EGCG is able to inhibit the hypermethylation of newly synthesised DNA, resulting in the reversal of hypermethylation and recovery in expression of the silenced genes. Reversion­inducing cysteine­rich protein with Kazal motifs (RECK) is a novel tumour suppressor gene, which negatively regulates matrix metalloproteinases, and inhibits tumour invasion, angiogenesis and metastasis. The present study aimed to examine the effects of EGCG on the methylation status of the RECK gene and tumour invasion in a salivary adenoid cystic carcinoma (SACC) cell line in vitro. Marked levels of methylated and weak levels of unmethylated RECK promoter were detected in the SACC83 cells, which was determined using methylation­specific polymerase chain reaction (PCR). In addition, the treatment of SACC83 cells with EGCG partially reversed the hypermethylation status of the RECK gene. Western blot analysis and reverse transcription­PCR demonstrated that EGCG significantly enhanced the protein and mRNA expression levels of RECK, and significantly reduced the invasive ability of the SACC83 cells, as determined using a Transwell assay. These results suggested that EGCG possesses novel anti­metastatic therapeutic potential for the treatment of SACC.

Lycorine suppresses RANKL-induced osteoclastogenesis in vitro and prevents ovariectomy-induced osteoporosis and titanium particle-induced osteolysis in vivo.

Osteoclasts play an important role in diseases involving bone loss. In this study, we assessed the effect of a plant-derived natural alkaloid (lycorine, or LY) on osteoclastogenesis in vitro and in vivo. Our in vitro study showed that receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis could be inhibited by LY; this effect was due to inhibition of mitogen-activated protein kinase (MAPK) signalling via MAP kinase kinases (MKKs). The MAPK agonist anisomycin could partially rescue the inhibitory effect of LY. Furthermore, LY also played a protective role in both a murine ovariectomy (OVX)-induced osteoporosis model and a titanium particle-induced osteolysis model. These results confirmed that LY was effective in preventing osteoclast-related diseases in vivo. In conclusion, our results show that LY is effective in suppressing osteoclastogenesis and therefore could be used to treat OVX-induced osteoporosis and wear particle-induced osteolysis.

ALDH2*2 Allele is a Negative Risk Factor for Cerebral Infarction in Chinese Women.

Unlike its reported role in the cardiovascular diseases, little information is available for mitochondrial aldehyde dehydrogenase 2 (ALDH2) in the cerebrovascular function. We investigated the different effects of ALDH2 genotypes on the risk of cerebral infarction between the genders, because different genders had different smoking and/or dinking status which are also risk factors for cerebral infarction. 247 healthy Chinese Han people (controls, group 1), 287 Chinese Han male patients with cerebral infarction (group 2), and 82 Chinese Han female patients with cerebral infarction (group 3) were involved in this study. The frequencies of the ALDH2*2 allele in group 3 were significantly higher than those in other groups (with P = 0.001 and P = 0.002, respectively). The difference of ALDH2*2 allele frequency between group 1 and group 2 was not significant (P = 0.652). After adjustment for smoking and drinking status, the male patients without smoking or drinking status (group 4) had higher ALDH2*2 allele frequency than group 1, but the difference was still not significant (P = 0.139). Thus, we conclude that ALDH2*2 allele may be a significant negative risk factor for cerebral infarction in Chinese women [odds ratio (OR) = 2.207, 95% CI 1.416-3.439]. But for Chinese male patients, the negative effects of ALDH2*2 allele on cerebral infarction which might be concealed by other risk factors were not significant.

Activation of AMPK participates hydrogen sulfide-induced cyto-protective effect against dexamethasone in osteoblastic MC3T3-E1 cells.

Long-time glucocorticoids (GCs) usage causes osteoporosis. In the present study, we explored the potential role of hydrogen sulfide (H2S) against dexamethasone (Dex)-induced osteoblast cell damage, and focused on the underlying mechanisms. We showed that two H2S-producing enzymes, cystathionine ß-synthase (CBS) and cystathionine γ-lyase (CSE), were significantly downregulated in human osteonecrosis tissues as well as in Dex-treated osteoblastic MC3T3-E1 cells. H2S donor NaHS as well as the CBS activator S-adenosyl-l-methionine (SAM) inhibited Dex-induced viability reduction, death and apoptosis in MC3T3-E1 cells. NaHS activated adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling, which participated its cyto-protective activity. AMPK inhibition by its inhibitor (compound C) or reduction by targeted-shRNA suppressed its pro-survival activity against Dex in MC3T3-E1 cells. Further, we found that NaHS inhibited Dex-mediated reactive oxygen species (ROS) production and ATP depletion. Such effects by NaHS were again inhibited by compound C and AMPKα1-shRNA. In summary, we show that H2S inhibits Dex-induced osteoblast damage through activation of AMPK signaling. H2S signaling might be further investigated as a novel target for anti-osteoporosis treatment.

Inhibition of both EGFR and IGF1R sensitized prostate cancer cells to radiation by synergistic suppression of DNA homologous recombination repair.

Reduced sensitivity of prostate cancer (PC) cells to radiation therapy poses a significant challenge in the clinic. Activation of epidermal growth factor receptor (EGFR), type 1 insulin-like growth factor receptor (IGF1R), and crosstalk between these two signaling pathways have been implicated in the development of radiation resistance in PC. This study assessed the effects of targeting both receptors on the regulation of radio-sensitivity in PC cells. Specific inhibitors of EGFR and IGF1R, Erlotinib and AG1024, as well as siRNA targeting EGFR and IGF1R, were used to radio-sensitize PC cells. Our results showed that co-inhibiting both receptors significantly dampened cellular growth and DNA damage repair, and increased radio-sensitivity in PC cells. These effects were carried out through synergistic inhibition of homologous recombination-directed DNA repair (HRR), but not via inhibition of non-homologous end joining (NHEJ). Furthermore, the compromised HRR capacity was caused by reduced phosphorylation of insulin receptor substrate 1 (IRS1) and its subsequent interaction with Rad51. The synergistic effect of the EGFR and IGF1R inhibitors was also confirmed in nude mouse xenograft assay. This is the first study testing co-inhibiting EGFR and IGF1R signaling in the context of radio-sensitivity in PC and it may provide a promising adjuvant therapeutic approach to improve the outcome of PC patients to radiation treatment.

Clinical application of CyberKnife for high-risk central nervous system tumors: A clinical trial report of 60 cases.

The objective of the present study was to evaluate the application potential of CyberKnife for high-risk tumors of the central nervous system and to analyze the effectiveness of CyberKnife in relation to dose recovery and gain division (times). A total of Eighty-one targeted areas from 139 central nervous tumor lesions in 60 patients were treated with I-VI ranged CyberKnife for 1 week. Following CyberKnife treatment, imaging tests revealed a decrease in tumor volume, reduction of central nervous system symptoms and an increase in the life quality of patients. The advantages of CyberKnife include non-invasiveness, individualized treatment, flexibility, high accuracy and rapid treatment. CyberKnife produces slight damage and a favorable therapeutic effect and expands our concepts concerning precise radiotherapy for tumors. It is an indispensable method for personalized tumor treatment.

Short-term outcomes of CyberKnife therapy for advanced high-risk tumors: A report of 160 cases.

The objective of the present study was to evaluate short-term outcomes of CyberKnife therapy in patients with advanced high-risk tumors. A total of 201 target areas from 341 advanced high-risk tumor lesions in 160 patients were treated with CyberKnife. A prescribed dose of 18-60 Gy to the gross tumor volume was delivered in 1-6 fractions to complete the entire treatment in 1 week. Radiographic studies and clinical examinations were performed at 1- to 3-month follow-up intervals, and the results were compared to outcomes of 160 similar advanced high-risk tumor patients who were treated by conformal radiotherapy (CRT). After CyberKnife therapy, the short-term improvement in the quality of life was significant according to radiographic study, radioimmunoassay and ZPS scores of these patients. The total rates of objective efficacy and alleviation of ascities were as high as 66.88 and 67.90%. The short-term outcomes in our series of patients with advanced high-risk tumors treated with CyberKnife appeared to be better compared to conventional CRT. CyberKnife may be an option for patients with incurable advanced high-risk tumors, although further studies of the long-term outcomes are required to confirm the validity.

Neuroprotective effects of new protein kinase C activator TPPB against Aß25₋35 induced neurotoxicity in PC12 cells.

Alzheimer's disease (AD) is pathologically characterized by presence of senile plaques in the hippocampus, which are composed mainly of extracellular deposition of a polypeptide known as the beta amyloid, the Aß. It has been demonstrated on numerous occasions that it was the deposition and aggregation of this Aß peptide that cause neuronal dysfunction and even finally, the dementia. Lowering the deposition of Aß or decreasing its neurotoxicity has long been one of the purposes of AD therapy. In previous study, we reported that protein kinase C (PKC) activator TPPB could regulate APP processing by increasing α-secretase activity. In this study we further investigated the potential neuroprotective effect of TPPB against Aß(25-35)-induced neurotoxicity in PC12 cells. The results indicated that TPPB at concentration of 1 µM could antagonize Aß(25-35) induced cell damage as evidenced by MTT assays, LDH release and by morphological changes. Furthermore, the neuroprotection in cell viability can be blocked by inhibitors of PKC, Akt and MAPK. The experiment also indicated that TPPB could increase the phosphorylation of Akt, PKC, MARCKS and MAPK, which were inhibited by Aß(25-35) treatment. Finally, TPPB inhibited the activation of caspase-3 induced by Aß(25-35). Taken together, the experiment here implies that TPPB has a role against Aß(25-35)-induced neurotoxicity in PC12 cells and may suggest its therapeutic potential in AD.

Suppression of MMP-9 activity by NDRG2 expression inhibits clear cell renal cell carcinoma invasion.

Members of the NDRG (N-Myc downstream-regulated) gene family have been shown to play a variety of roles in human malignancies. Recently, it was shown decreased expression in clear cell renal cell carcinoma (CCRCC) and inhibited cell proliferation, but the role of the NDRG2 in CCRCC invasion has not been described. We examined the expression of NDRG2 protein in CCRCC samples and the association between NDRG2 expression and CCRCC patients survival. Real-time RT-PCR and immunohistochemical analysis were used to measure NDRG2 expression in 60 paired CCRCC and adjacent normal tissues. Changes in cell invasion were detected by up- or down-regulating NDRG2 by adenovirus or siRNA. We found that NDRG2 expression is significantly down-regulated in CCRCC at mRNA and protein levels in a manner negatively associated with aggressive tumor behaviors, such as TNM stage (P = 0.003), Fuhrman's grade (P = 0.024), tumor invasion (P = 0.001) and tumor recurrence (P = 0.004), as well as shorter patient survival rates (P = 0.0041). Furthermore, NDRG2 could suppress CCRCC cell invasion through regulating MMP-9 expression and activity. So, these results suggest that NDRG2 can inhibit extracellular matrix-based tumor cell invasion and thereby play important roles in suppressing tumor metastasis in CCRCC. NDRG2 expression may also be a significant prognostic indicator for CCRCC.

NDRG2 suppresses the proliferation of clear cell renal cell carcinoma cell A-498.

BACKGROUND: Recently, the anti-tumor activity of N-myc downstream-regulated gene 2 (NDRG2) was shown decreased expression in clear cell renal cell carcinoma (CCRCC), but the role of the down-expression of NDRG2 has not been described. METHODS: The NDRG2 recombinant adenovirus plasmid was constructed. The proliferation rate and NDRG2 expression of cell infected with recombinant plasmid were mesured by MTT, Flow cytometry analysis and western blot. RESULTS: The CCRCC cell A-498 re-expressed NDRG2 when infected by NDRG2 recombinant adenovirus and significantly decreased the proliferation rate. Fluorescence activated cell sorter analysis showed that 25.00% of cells expressed NDRG2 were in S-phase compared to 40.67% of control cells, whereas 62.08% of cells expressed NDRG2 were in G1-phase compared to 54.39% of control cells (P < 0.05). In addition, there were much more apoptotic cells in NDRG2-expressing cells than in the controls (P < 0.05). Moreover, upregulation of NDRG2 protein was associated with a reduction in cyclin D1, cyclin E, whereas cyclinD2, cyclinD3 and cdk2 were not affected examined by western blot. Furthermore, we found that p53 could upregulate NDRG2 expression in A-498 cell. CONCLUSIONS: We found that NDRG2 can inhibit the proliferation of the renal carcinoma cells and induce arrest at G1 phase. p53 can up-regulate the expression of NDRG2. Our results showed that NDRG2 may function as a tumor suppressor in CCRCC.

[Treatment of condylar fracture by external pterygoid muscle-condyle anatomical reduction and internal rigid fixation with mini titanium plates].

PURPOSE: To investigate the surgical indications, procedures and treatment outcomes of condylar fracture by external pterygoid muscle-condyle anatomical reduction and internal rigid fixation with mini titanium plates. METHODS: Patients with dislocation of the condylar head, fracture of the condylar neck and subcondylar neck (the degree of displacement greater than 30 to 45) and decreased vertical height of the ramus (greater than 4 to 5mm) were included in the study. Modified aural-temporal stick-shaped incision or retromandibular approach was adopted in 23 cases with 28 condylar fractures. The fractures were treated by external pterygoid muscle-condyle anatomical reduction and internal rigid fixation with mini tension band titanium plates. All the patients were re-examined and evaluated 3 to 6 months after surgery in respects of facial symmetry, mouth opening, types of mouth opening, occlusion and mastication. RESULTS: All the patients had symmetrical face, mouth opening increased from 26.7+/-7.2 (before surgery) to 38.4+/-5.6 (3 months after surgery) and 37.2+/-4.5 mm(6 months after surgery). 2 patients with postoperative malocclusion had intermaxillary distraction for 1 week and their occlusion returned to normal. Radiographic check-up showed the condyle and titanium plates without displacement. No absorption was noted on the condylar surface. The patients had normal mastication. 2 patients with temporal facial paralysis recovered 3 months after conservative therapy. CONCLUSION: Treatment of condylar fracture by external pterygoid muscle-condyle anatomical reduction and internal rigid fixation with mini titanium plates in selected patients is an effective procedure for recovery of anatomical positions and masticatory function. Supported by Research Fund from Science and Technology Bureau of Jining city.