Efficacy and safety of EGFR­TKIs plus Shenqi Fuzheng injection for non-small cell lung cancer patients with EGFR-sensitive mutations.

PURPOSE: The aim of this retrospective study is to evaluate the impact on efficacy and safety between epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) alone and in combination with Shenqi Fuzheng injection (SFI) in patients with advanced NSCLC harboring epidermal growth factor receptor (EGFR) activating mutations. METHODS: Retrospectively, information of 88 patients receiving EGFR-TKIs as first-line targeted treatment or in combination with SFI in the Affiliated Drum Tower Hospital of Nanjing University Medical College and the Affiliated Cancer Hospital of Anhui University of Science and Technology was collected. The primary endpoint was to assess progression-free survival (PFS) and safety of EGFR-TKIs alone or in combination with SFI. RESULTS: Between January 2016 and December 2019, a total of 88 patients were enrolled in this research, including 50 cases in the EGFR-TKIs single agent therapy group and 38 cases in the SFI combined with EGFR-TKIs targeted-therapy group. The median PFS (mPFS) of monotherapy group was 10.50 months (95%CI 9.81-11.19), and 14.30 months (95%CI 10.22-18.38) in the combination therapy group. Compared to the single EGFR-TKIs administration, combinational regimen with SFI exhibited a lower incidence of rash and diarrhea in patients and was even better tolerated. CONCLUSIONS: SFI combined with the first-generation EGFR-TKIs are more efficient, can prominently prolong the PFS and attenuate the adverse reactions in patients with advanced NSCLC with EGFR-sensitive mutations.

PPARα agonist fenofibrate relieves acquired resistance to gefitinib in non-small cell lung cancer by promoting apoptosis via PPARα/AMPK/AKT/FoxO1 pathway.

Recent studies show that intracellular accumulation of cholesterol leads to acquired resistance to gefitinib in non-small cell lung cancer (NSCLC) cells. In this study we investigated how to regulate the cholesterol levels in gefitinib-resistant NSCLC cells. We showed that intracellular cholesterol levels in gefitinib-resistant cell lines (PC-9/GR, H1975, H1650, and A549) were significantly higher than that in gefitinib-sensitive cell line (PC-9). Treatment with gefitinib (5 µM) significantly increased intracellular cholesterol levels in PC-9/GR, H1975, and H1650 cells. Gefitinib treatment downregulated the expression of PPARα, LXRα, and ABCA1, leading to dysregulation of cholesterol efflux pathway. We found that a lipid-lowering drug fenofibrate (20, 40 µM) dose-dependently increased the expression of PPARα, LXRα, and ABCA1, decreased the intracellular cholesterol levels, and enhanced the antiproliferative effects of gefitinib in PC-9/GR, H1975, and H1650 cells. We revealed that fenofibrate increased the gefitinib-induced apoptosis via regulating the key proteins involved in the intrinsic apoptosis pathway. In PC-9/GR, H1975 and H1650 cells, fenofibrate dose-dependently increased the expression of AMPK, FoxO1, and decreased the expression of AKT, which were remarkably weakened by knockdown of PPARα. In PC-9/GR cell xenograft mice, combined administration of gefitinib (25 mg · kg-1 · d-1) and fenofibrate (100 mg · kg-1 · d-1) caused remarkable inhibition on tumor growth as compared to treatment with either drug alone. All the results suggest that fenofibrate relieves acquired resistance to gefitinib in NSCLC by promoting apoptosis via regulating PPARα/AMPK/AKT/FoxO1 pathway. We propose that combination of gefitinib and fenofibrate is a potential strategy for overcoming the gefitinib resistance in NSCLC.

Integrated analysis of miRNAs and transcriptomes in Aedes albopictus midgut reveals the differential expression profiles of immune-related genes during dengue virus serotype-2 infection.

Mosquito microRNAs (miRNAs) are involved in host-virus interaction, and have been reported to be altered by dengue virus (DENV) infection in Aedes albopictus (Diptera: Culicidae). However, little is known about the molecular mechanisms of Aedes albopictus midgut-the first organ to interact with DENV-involved in its resistance to DENV. Here we used high-throughput sequencing to characterize miRNA and messenger RNA (mRNA) expression patterns in Aedes albopictus midgut in response to dengue virus serotype 2. A total of three miRNAs and 777 mRNAs were identified to be differentially expressed upon DENV infection. For the mRNAs, we identified 198 immune-related genes and 31 of them were differentially expressed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses also showed that the differentially expressed immune-related genes were involved in immune response. Then the differential expression patterns of six immune-related genes and three miRNAs were confirmed by real-time reverse transcription polymerase chain reaction. Furthermore, seven known miRNA-mRNA interaction pairs were identified by aligning our two datasets. These analyses of miRNA and mRNA transcriptomes provide valuable information for uncovering the DENV response genes and provide a basis for future study of the resistance mechanisms in Aedes albopictus midgut.

Effect of Elbow Position on Short-segment Nerve Conduction Study in Cubital Tunnel Syndrome.

BACKGROUND: The appropriate elbow position of short-segment nerve conduction study (SSNCS) to diagnose cubital tunnel syndrome (CubTS) is still controversial. The goal of this study was to determine the effect of different elbow positions at full extension and 70° flexion on SSNCS in CubTS. METHODS: In this cross-sectional study, the clinical data of seventy elbows from 59 CubTS patients between September, 2011 and December, 2014 in the Peking University First Hospital were included as CubTS group. Moreover, thirty healthy volunteers were included as the healthy group. SSNCS were conducted in all subjects at elbow full extension and 70° elbow flexion. Paired nonparametric test, bivariate correlation, Bland-Altman, and Chi-squared test analysis were used to compare the effectiveness of elbow full extension and 70° flexion elbow positions on SSNCS in CubTS patients. RESULTS: Data of upper limit was calculated from healthy group, and abnormal latency was judged accordingly. CubTS group's latency and compound muscle action potential (CMAP) of each segment at 70° elbow flexion by SSNCS was compared with full extension position, no statistically significant difference were found (all P > 0.05). Latency and CMAP of each segment at elbow full extension and 70° flexion were correlated (all P < 0.01), except the latency of segment of 4 cm to 6 cm above elbow (P = 0.43), and the latency (P = 0.15) and the CMAP (P = 0.06) of segment of 2 cm to 4 cm below elbow. Bivariate correlation and Bland-Altman analysis proved the correlation between elbow full extension and 70° flexion. Especially in segments across the elbow (2 cm above the elbow and 2 cm below it), latency at elbow full extension and 70° flexion were strong direct associated (r = 0.83, P < 0.01; r = 0.55, P < 0.01), and so did the CMAP (r = 0.49, P < 0.01; r = 0.72, P < 0.01). There was no statistically significant difference in abnormality of each segment at full extension as measured by SSNCS compared with that at 70° flexion (P > 0.05, respectively). CONCLUSIONS: There was no statistically significant difference in the diagnosis of CubTS with the elbow at full extension compared with that at 70° flexion during SSNCS. We suggest that elbow positon at full extension can also be used during SSNCS.

Preliminary study on the lesion location and prognosis of cubital tunnel syndrome by motor nerve conduction studies.

BACKGROUND: To study lesions' location and prognosis of cubital tunnel syndrome (CubTS) by routine motor nerve conduction studies (MNCSs) and short-segment nerve conduction studies (SSNCSs, inching test). METHODS: Thirty healthy subjects were included and 60 ulnar nerves were studied by inching studies for normal values. Sixty-six patients who diagnosed CubTS clinically were performed bilaterally by routine MNCSs and SSNCSs. Follow-up for 1-year, the information of brief complaints, clinical symptoms, and physical examination were collected. RESULTS: Sixty-six patients were included, 88 of nerves was abnormal by MNCS, while 105 was abnormal by the inching studies. Medial epicondyle to 2 cm above medial epicondyle is the most common segment to be detected abnormally (59.09%), P < 0.01. Twenty-two patients were followed-up, 17 patients' symptoms were improved. Most of the patients were treated with drugs and modification of bad habits. CONCLUSIONS: (1) SSNCSs can detect lesions of compressive neuropathy in CubTS more precisely than the routine motor conduction studies. (2) SSNCSs can diagnose CubTS more sensitively than routine motor conduction studies. (3) In this study, we found that medial epicondyle to 2 cm above the medial epicondyle is the most vulnerable place that the ulnar nerve compressed. (4) The patients had a better prognosis who were abnormal in motor nerve conduction time only, but not amplitude in compressed lesions than those who were abnormal both in velocity and amplitude. Our study suggests that SSNCSs is a practical method in detecting ulnar nerve compressed neuropathy, and sensitive in diagnosing CubTS. The compound muscle action potentials by SSNCSs may predict prognosis of CubTS.

Longikaurin E induces apoptosis of pancreatic cancer cells via modulation of the p38 and PI3K/AKT pathways by ROS.

Pancreatic cancer is a devastating disease with a poor prognosis. It ranks as the fourth or fifth most common cancer in men and women and has the lowest 5-year survival rate. Therefore, there is an urgent need to develop novel therapeutic agents for pancreatic cancer. Longikaurin E (LE), which is derived from the traditional herbal medicine Rabdosia longituba, had been reported to have anti-proliferative and pro-apoptotic properties in several types of cancers. In this study, we investigated the cytotoxic properties of LE against pancreatic cancer cells and explored the mechanism behind the observed apoptosis. Pancreatic cancer cell lines cultured in the presence of LE exhibited dose- and time-dependent growth suppression by clone formation, methylthiazoltetrazolium assay, lactate dehydrogenase cytotoxicity assay, and fluorescence-activated cell sorting analysis, respectively. In addition, these culture conditions also induced the generation of cellular reactive oxygen species (ROS). In order to determine the mechanisms underlying LE-induced cytotoxicity, we used reverse transcription polymerase chain reaction and Western blot analysis in the pancreatic cancer cell line PANC1. The results showed that the expression of Bax was noticeably upregulated and the expression levels of Bcl-2, Bcl-XL, survivin, and c-Myc were significantly downregulated. We also observed increased p38 phosphorylation and decreased phosphorylation of the PI3K/AKT pathway. Interestingly, we also found that LE activated caspase-3. However, N-acetyl-L-cysteine, a kind of antioxidant, reversed all of these cellular activities. In conclusion, this study suggested that LE induced apoptosis of pancreatic cancer cells via ROS generation to modulate the p38 and PI3K/AKT pathways and could be a promising anti-pancreatic agent.

Significance of quantitative sensory testing in the diagnosis of diabetic peripheral neuropathy.

PURPOSE: To investigate the significance of quantitative sensory testing in the diagnosis of early diabetic peripheral neuropathy. METHODS: One hundred ninety-six patients with diabetes with neurological deficits were determined by nerve conduction studies and quantitative sensory testing. Seventy-seven age-matched healthy controls were determined by quantitative sensory testing. Results were analyzed statistically. RESULTS: Cold thresholds of shorter-term patients (course of disease ≤ 5 years) were lower than controls. Warm thresholds of longer-term patients (course of disease >5 years) were higher than with shorter-term patients. Warm thresholds of patients with normal nerve conduction studies were higher than controls (P < 0.05). The frequency of abnormality of quantitative sensory testing of longer-term patients was higher than with shorter duration patients. The frequency of abnormality was 36.7% and 72.3%, respectively, in the dorsum (P < 0.05). CONCLUSIONS: Quantitative sensory testing is sensitive for the diagnosis of diabetic peripheral neuropathy, especially for warm thresholds in the dorsum of the foot. Quantitative sensory testing is necessary to assist nerve conduction studies in the diagnosis of early diabetic peripheral neuropathy.

[Prevention against and treatment of doxorubicin-induced acute cardiotoxicity by dexrazoxane and schisandrin B].

In this study, it is to compare the effectiveness of prevention against and treatment of doxorubicin (DOX) induced cardiotoxicity by dexrazoxane and schisandrin B (Sch B) in rats. Sprague-Dawley (SD) rats were randomly divided into the following 6 groups: normal saline group, DOX group, DOX+DEX group, DOX+Sch B (80 mg x kg(-1)) group, DOX+Sch B (40 mg x kg(-1)) group and DOX+Sch B (20 mg x kg(-1)) group. The results showed that Sch B could combat the increase of myocardial enzymes in peripheral blood, decrease of the enzyme activity of myocardial tissue antioxidant enzymes and disorders of systolic and diastolic function of heart in rats intravenously injected with doxorubicin (15 mg x kg(-1)). Sch B was better than DEX in protecting rat against DOX-induced the symptoms. Sch B could protect rat against DOX-induced acute cardiomyopathy and has clinical potential applications.

The synthetic melanocortin (CKPV)2 exerts anti-fungal and anti-inflammatory effects against Candida albicans vaginitis via inducing macrophage M2 polarization.

In this study, we examined anti-fungal and anti-inflammatory effects of the synthetic melanocortin peptide (Ac-Cys-Lys-Pro-Val-NH2)2 or (CKPV)2 against Candida albicans vaginitis. Our in vitro results showed that (CKPV)2 dose-dependently inhibited Candida albicans colonies formation. In a rat Candida albicans vaginitis model, (CKPV)2 significantly inhibited vaginal Candida albicans survival and macrophages sub-epithelial mucosa infiltration. For mechanisms study, we observed that (CKPV)2 inhibited macrophages phagocytosis of Candida albicans. Meanwhile, (CKPV)2 administration inhibited macrophage pro-inflammatory cytokines (TNF-α, IL-1ß and IL-6) release, while increasing the arginase activity and anti-inflammatory cytokine IL-10 production, suggesting macrophages M1 to M2 polarization. Cyclic AMP (cAMP) production was also induced by (CKPV)2 administration in macrophages. These above effects on macrophages by (CKPV)2 were almost reversed by melanocortin receptor-1(MC1R) siRNA knockdown, indicating the requirement of MC1R in the process. Altogether, our results suggest that (CKPV)2 exerted anti-fungal and anti-inflammatory activities against Candida albicans vaginitis probably through inducing macrophages M1 to M2 polarization and MC1R activation.

[Diagnostic significance of spinal cord conduction velocity in the diagnosis of central lesions in subacute combined degeneration].

OBJECTIVE: To study explore the roles of spinal cord conduction velocity (SCCV) test in the diagnosis of spinal lesions in patients with subacute combined degeneration (SCD) of spinal cord and examine the values of SCCV in the localization of spinal lesions. METHODS: A total of 22 SCD patients recruited from 2005 to 2010 at our hospital underwent the SCCV test, the somatosensory evoked potential (SEP) test and MRI in spinal cord respectively. The results of SCCV were compared with those of SEP and MRI. RESULTS: There were 16 males and 6 females with an average age of (56 ± 13) years old (range: 28 - 84). All SCD patients underwent the examinations of SCCV and spinal MRI. And 18 patients received the test of SEP. The abnormalities of SCCV test were 81.8% (18/22) and those of MRI and SEP 13.6% (3/22) and 72.2% (13/15) respectively. The results of SCCV and spinal MRI were both abnormal in 3 patients. Nineteen patients had normal MRI while 18 had abnormal SCCV results. CONCLUSION: The early electrophysiological abnormalities in spinal cord of SCD patients may be detected objectively by SCCV. They appear earlier than those of pathological and imaging findings. The abnormal rates of SCCV are much higher than those of spinal MRI. The SCCV test can also help to localize the lesions in spinal cord of SCD patients. It may provide an objective diagnostic basis for the lesions of spinal cord of SCD patients at an early stage.

[Significance of sympathetic skin response in diagnosis diabetic small fiber neuropathy].

OBJECTIVE: To investigate the significance of sympathetic skin response (SSR) in the diagnosis of diabetic small fiber neuropathy. METHODS: 38 diabetic patients with paraesthesia and 30 healthy controls underwent SSR test on the 4 limbs. The latencies of the initiation and waves N and P of SSR were analyzed. The results of nerve conduction velocities of these patients with paraesthesia were normal. RESULTS: The latencies of the initiation and waves N or P in SSR were prolonged in 37 limbs of the 38 patients, and there was no SSR response in 21 limbs. The latencies of the initiation and waves N and P of SSR test in both upper extremity and lower extremities were prolonged significantly in the diabetic patients as compared to the controls (all P < 0.05). The frequency of abnormality in the latency of SSR was 51% in the lower extremities, and 38% in the upper extremities. The frequency of abnormal latency of SSR in the lower extremities was higher, however, not significantly, than that in the upper extremities (P > 0.05). Twenty-eight of the 38 patients (74%) demonstrated abnormal SSR in at least one limbs. CONCLUSION: SSR can be used to detect the early dysfunction of the small fibers in diabetic peripheral neuropathy, especially in the diabetic patients with normal nerve conduction velocities. SSR test may be a useful and sensitive neuroelectrophysiologic testing for the early diagnosis of diabetic small fiber neuropathy.

[The cerebral function monitoring in severe cerebral vascular disease].

OBJECTIVE: To evaluate the value of combined evoked potential, continuous EEG with transcranial Doppler to monitor the cases of severe cerebral vascular disease. METHODS: 32 cases of severe cerebral vascular disease were admitted to the hospital and divided into severe or moderate groups based on the GCS (< or = or > 8) when the patients were admitted. BAEP and SEP were used to for monitoring of brain and brainstem functions. The BAEP and SEP results were divided into grade I, grade II and grade III according to Cant's classification. Continuous EEG monitored all patients by bedside. The EEG findings were divided into 6 grades based on Young's criteria. TCD monitoring by using bilateral 2 MHz Probes with probe holder were lasted at least 30 minutes per day through temporal windows and eye windows to explore the velocity of cerebral artery. The patients were classified into three groups according to the velocities, i.e. (1) the group with elevated velocity, (2) the group with reduced velocity, and (3) the group with normal velocity. The association among the brain and brain stem function, cortex function and cerebral flow velocity was analyzed with patient outcome in the two groups. RESULTS: (1) The mortality of the patients in the severe group was 42.86%, significantly higher than that in the group of moderate symptom (22.22%). The survivors with good outcome accounted for 33.33% in the moderate group, and those with independent disability accounted for 44.44% in the moderate group, much better than those in the severe group. (2) The numbers of the patients with III grade SEP and BAEP results in the severe group were higher than those in the moderate group. The mortality of the patients with III grade SEP and BAEP results was high and the most of survivors were found with obvious disability in outcome. The patients with grade I SEP and BAEP results showed a better outcome. (3) 32 patients of cerebral vascular disease were monitored with continuous EEG monitoring by bedside. The results revealed that the mortality of the patients with grade II EEG results was much higher than that of the patients with grade I EEG results. (4) The association of the brain blood flow velocity, either increased or decreased or within normal range was uncertain (all P > 0.05). CONCLUSION: The cerebral function of patients of severe cerebral vascular disease may be estimated precisely and objectively by using continuous monitoring of SEP, BAEP and EEG at bedside, which will provide valuable information about patient's prognosis and treatment.

Pathogenesis and electrodiagnosis of cubital tunnel syndrome.

BACKGROUND: Cubital tunnel syndrome is a well-recognized clinical condition and is the second most common peripheral compression neuropathy. This study was designed to investigate the causes of cubital tunnel syndrome by surgical means and to assess the clinical value of the neurophysiological diagnosis of cubital tunnel syndrome. METHODS: Twenty-one patients (involving a total of 22 limbs from 16 men and 5 women, aged 22 to 63, with a mean age of 49 years) with clinical symptoms and signs indicating a problem with their ulnar nerve underwent motor conduction velocity examinations at different sites along the ulnar nerve and examinations of sensory conduction velocity in the hand, before undergoing anterior transposition of the ulnar nerve. RESULTS: Electromyographic abnormalities were seen in 21 of 22 limbs [motor nerve conduction velocity (MCV) range (15.9 - 47.5) m/s, mean 32.7 m/s] who underwent motor conduction velocity examinations across the elbow segment of the ulnar nerve. Reduced velocity was observed in 13 of 22 limbs [MCV (15.7 - 59.6) m/s, mean 40.4 m/s] undergoing MCV tests in the forearms. An absent or abnormal sensory nerve action potential following stimulation was detected in the little finger of 14 of 22 limbs. The factors responsible for ulnar compression based on observations made during surgery were as follows: 15 cases involved compression by arcuate ligaments, muscle tendons, or bone hyperplasia; 2 involved fibrous adhesion; 3 involved compression by the venous plexus or a concurrent thick vein; 2 involved compression by cysts. CONCLUSIONS: Factors inducing cubital tunnel syndrome include both common factors that have been reported and rare factors, involving the venous plexus, thick veins, and cysts. Tests of motor conduction velocity at different sites along the ulnar nerve should be helpful in diagnosis cubital tunnel syndrome, especially MCV tests indicating decreased velocity across the elbow segment of the ulnar nerve.

Value of sympathetic skin response test in the early diagnosis of diabetic neuropathy.

BACKGROUND: Diabetic neuropathy is common in diabetes mellitus. The early stage of diabetic neuropathy is often symptomless and difficult to be treated. The aim of this study was to assess the correlation between the results of the sympathetic skin response (SSR) test and the development of diabetic neuropathy, and explore the use of SSR as an objective basis for the early diagnosis of diabetic neuropathy. METHODS: The latencies and amplitudes of initiation and of the N and P waves were determined by SSR testing of the extremities of 80 diabetic patients and 30 healthy controls. RESULTS: The latencies of initiation and of the N and P waves were significantly (P <0.001) longer in diabetic patients than in the controls, while there was no significant difference in the amplitudes (P >0.05). All but two patients (97.5%) demonstrated abnormal SSR in at least one limb. CONCLUSIONS: SSR can detect early dysfunction of the small sympathetic fibers in people affected by diabetes mellitus, and may be a useful electrophysiological test for the early diagnosis of diabetic neuropathy.