Chemotherapy-induced peripheral neurotoxicity (CIPN) is a severe dose-limiting adverse event of chemotherapy. Presently, the mechanism underlying the induction of CIPN remains unclear, and no effective treatment is available. In this study, through metabolomics analyses, we found that nab-paclitaxel therapy markedly increased serum serotonin [5-hydroxtryptamine (5-HT)] levels in both cancer patients and mice compared to the respective controls. Furthermore, nab-paclitaxel-treated enterochromaffin (EC) cells showed increased 5-HT synthesis, and serotonin-treated Schwann cells showed damage, as indicated by the activation of CREB3L3/MMP3/FAS signaling. Venlafaxine, an inhibitor of serotonin and norepinephrine reuptake, was found to protect against nerve injury by suppressing the activation of CREB3L3/MMP3/FAS signaling in Schwann cells. Remarkably, venlafaxine was found to significantly alleviate nab-paclitaxel-induced CIPN in patients without affecting the clinical efficacy of chemotherapy. In summary, our study reveals that EC cell-derived 5-HT plays a critical role in nab-paclitaxel-related neurotoxic lesions, and venlafaxine co-administration represents a novel approach to treating chronic cumulative neurotoxicity commonly reported in nab-paclitaxel-based chemotherapy.
Paclitaxel/toxicity* ; Animals ; Albumins/adverse effects* ; Serotonin/metabolism* ; Mice ; Humans ; Male ; Female ; Venlafaxine Hydrochloride/therapeutic use* ; Neurotoxicity Syndromes/metabolism* ; Middle Aged ; Schwann Cells/metabolism* ; Peripheral Nervous System Diseases/drug therapy* ; Antineoplastic Agents

Objective:To analyze the clinicopathological characteristics of IgG4-related sialadenitis (IgG4-RS).Methods:A total of 40 cases diagnosed with IgG4-RS were collected from the Department of Oral Pathology, Shanghai Ninth People′s Hospital, Shanghai Jiao Tong University School of Medicine from January 2019 to December 2022. Among them, there were 26 males and 14 females. The age range was 29-77 years old [(59.4±11.8) years old], with 23 patients being older than 60 years. The lesion site, imaging manifestations, histopathological features, serological test and treatment information of patients were collected. The expression of IgG4 and IgG proteins was detected by immunohistochemistry.Results:Submandibular region swelling was the most common initial symptom of IgG4-RS (38/40, 95.0%). All the patients having serum IgG4 levels> 1.35 g/L. Serum IgG4 levels were significantly increased in patients aged>60 years ( Z=-2.45, P=0.014) and those involving multiple glands ( Z=-2.04, P=0.042). Thirty six cases received major salivary gland biopsy, and all the cases showed dense lymphocyte and plasma cell infiltration. Lymphoid follicle, storiform fibrosis and obliterative phlebitis were seen in 88.9% (32/36), 63.9% (23/36), 30.6% (11/36) of the cases, respectively. Twenty one cases received labial salivary gland biopsy, 66.7% (14/21) showed lymphocyte and plasma cell infiltration, 19.0% (4/21) had lymphoid follicle structures, and 33.3% (7/21) showed no obvious histological abnormalities. No signs of fibrosis or obliterative phlebitis were observed in all labial salivary gland biopsies. And 95.0% (38/40) of cases had IgG4 positive plasma cell>10/HPF, 82.5% (33/40) of cases had IgG4/IgG positive plasma cell ratio>40%. All the patients had a decrease in serum IgG4 levels after glucocorticoid treatment, but only 21.4% (6/28) of cases had reduced to normal levels (≤1.35 g/L), and there were still significant fluctuations in serum IgG4 levels thereafter. Conclusions:IgG4-RS has a predilection for middle-aged and elderly male patients, and serum IgG4 levels are significantly related to the patient′s age and whether multiple glands are involved. Labial salivary gland biopsy cannot replace submandibular gland for histopathological evaluation. It is a common phenomenon that serum IgG4 levels cannot restored to normal levels after glucocorticoid treatment. This study provides certain assistance for clinical and pathological diagnosis of IgG4-RS. This study is beneficial for further understanding IgG4-RS and improving the clinical and pathological diagnosis of the disease.

The emergence of SARS-CoV-2 variants of concern and repeated outbreaks of coronavirus epidemics in the past two decades emphasize the need for next-generation pan-coronaviral therapeutics. Drugging the multi-functional papain-like protease (PLpro) domain of the viral nsp3 holds promise. However, none of the known coronavirus PLpro inhibitors has been shown to be in vivo active. Herein, we screened a structurally diverse library of 50,080 compounds for potential coronavirus PLpro inhibitors and identified a noncovalent lead inhibitor F0213 that has broad-spectrum anti-coronaviral activity, including against the Sarbecoviruses (SARS-CoV-1 and SARS-CoV-2), Merbecovirus (MERS-CoV), as well as the Alphacoronavirus (hCoV-229E and hCoV-OC43). Importantly, F0213 confers protection in both SARS-CoV-2-infected hamsters and MERS-CoV-infected human DPP4-knockin mice. F0213 possesses a dual therapeutic functionality that suppresses coronavirus replication via blocking viral polyprotein cleavage, as well as promoting antiviral immunity by antagonizing the PLpro deubiquitinase activity. Despite the significant difference of substrate recognition, mode of inhibition studies suggest that F0213 is a competitive inhibitor against SARS2-PLpro via binding with the 157K amino acid residue, whereas an allosteric inhibitor of MERS-PLpro interacting with its 271E position. Our proof-of-concept findings demonstrated that PLpro is a valid target for the development of broad-spectrum anti-coronavirus agents. The orally administered F0213 may serve as a promising lead compound for combating the ongoing COVID-19 pandemic and future coronavirus outbreaks.
Animals ; Coronavirus Papain-Like Proteases/antagonists & inhibitors* ; Cricetinae ; Humans ; Mice ; Pandemics ; SARS-CoV-2/enzymology* ; COVID-19 Drug Treatment

Objective:To study the expression of programmed death ligand-1 (PD-L1) in tumor cells and CD8 +T lymphocytes in tumor infiltrating lymphocytes, and to analyze the correlation of PD-L1 expression with infiltration of CD8 +T lymphocytes and clinicopathologic features in salivary gland lymphoepithelial carcinoma (LEC). Methods:Forty-two cases of primary salivary LECs and 21 cases of secondary salivary LECs were enrolled at the Department of Oral Pathology, Shanghai Ninth People′s Hospital, Shanghai Jiaotong University between 2015 and 2017. The expression of Epstein-Barr (EB) virus, PD-L1 and CD8 was examined using chromogenic in situ hybridization (CISH) and immunohistochemistry (IHC) staining. The data were analyzed using SPSS 23.0 software package.Results:EB virus was detected in 61 cases (61/63, 96.8%), including 42 (42/42, 100%) primary LECs and 19 (19/21, 90.5%) secondary LECs. The PD-L1 positive rate (score ≥1) was 97.6% (41/42), and its high-expression rate (score ≥20) was 78.6% (33/42) in primary LECs. The PD-L1 positive rate (score ≥1) was 71.4% (15/21), and its high-expression rate (≥20) was 38.1% (8/21) in secondary LECs. However, the PD-L1 positive rate (score ≥1, P=0.004) and high-expression rate (score ≥20, P=0.001) in primary LECs were higher than those in secondary LECs. There was no difference in the infiltration degree of CD8 +T lymphocytes between primary and secondary LECs. There was a significant correlation between the expression of PD-L1 and CD8 in primary LECs ( P=0.001) and in secondary LECs ( P=0.048), respectively. Conclusions:There is PD-L1 expression in primary and secondary salivary LECs, while the expression rate is higher in primary LECs than secondary LECs. The combination of PD-L1 expression and CD8 +T lymphocytes′ presence suggest that most LEC patients might be responsive to immunotherapy, and primary LECs might be more significantly responsive than secondary LECs.

Objective:To evaluate the effect of angiotensin-converting enzyme (ACE) gene polymorphism on dexmedetomidine-induced inhibition of responses to endotracheal intubation in the patients with hypertension.Methods:One hundred and eighty patients with essential hypertension, aged 48-61 yr, weighing 51-66 kg, of American Society of Anesthesiologists physical status Ⅱ or Ⅲ, in whom ACE genotype was determined using polymerase chain reaction-restriction fragment length polymorphisms method before operation, were divided into 6 groups ( n=30 each) according to whether dexmedetomidine was applied: DD genotype group (DD group), ID genotype group (ID group), II genotype group (II group), dexmedetomidine plus DD genotype group (DEX+ DD group), dexmedetomidine plus ID genotype group (DEX+ ID group), and dexmedetomidine plus II genotype group (DEX+ II group). Dexmedetomidine 0.8 μg/kg was intravenously infused over 15 min before induction of anesthesia in DEX+ DD group, DEX+ ID group and DEX+ II group.Systolic and diastolic pressure (SP, DP) and heart rate (HR) were measured before dexmedetomidine (T 0), immediately before tracheal intubation (T 1), immediately after tracheal intubation (T 2), and at 1.5 and 5.0 min after tracheal intubation (T 3, 4). The rate-pressure product (RPP) was calculated.The occurrence of myocardial ischemia and cardiovascular responses within 5 min after tracheal intubation was recorded.Blood samples from the internal jugular vein were collected at T 0 and T 2-4, and plasma concentrations of epinephrine (E) and norepinephrine (NE) were determined by high performance liquid chromatography-electrochemical detection assay. Results:Compared with group DD, the SP, DP, HR and RPP were significantly decreased at T 2-4, plasma NE and E concentrations were decreased at T 2, 3, and the incidence of myocardial ischemia and cardiovascular reactions was decreased in group Dex+ DD ( P<0.05). Compared with group ID, SP, DP, HR and RPP were significantly decreased at T 2-4, plasma NE and E concentrations were decreased at T 2, 3, and the incidence of myocardial ischemia and cardiovascular responses were decreased in group Dex+ DD ( P<0.05). Compared with group II, SP, DP, HR and RPP were significantly decreased at T 2, 3, plasma NE and E concentrations were decreased, HR and RPP were decreased at T 4, and the incidence of myocardial ischemia and cardiovascular reactions was decreased in group Dex+ II ( P<0.05). There was no significant difference in the above parameters among group Dex+ DD, group Dex+ ID and group Dex+ II ( P>0.05). Conclusion:ACE gene polymorphism does not affect dexmedetomidine-induced inhibition of responses to endotracheal intubation in the patients with hypertension.

Objective To investigate ablation characteristics of PVC/VT originating from left ventricle anterior papillary muscles.Methods This study included 10 patients of PVC/VT originating from left ventricle anterior papillary muscles from January 2015 to June 2016 in Beijing Anzhen Hospital.Electrophysiological mapping and radiofrequency ablation were completed using three-dimensional anatomical mapping system combined with three-dimensional intracardiac ultrasound technology.ECG and abaltion target diagram characteristics as well as the special anatomy were explored.Results All the 10 patients were successfully ablated and followed up for 12 months.One patient had recurrence within 12 months and no complications were recorded.The target sites localized at the tip (n =1),middle portion(n =4)or the base (n =5) of the LV-APM.Among 7 patients,the target sites were located at the anterior septal papillary muscle and in 3 patients were located in the free papillary muscle.9 patients were successfully ablated via anterograde trans-septal catheterization after the failure of retrograde approach.Premature QRS wave time were 152.80 ± 11.72 ms and 6 patients presented sharp potential at the targets during PVC/VT.Conclusions PVC/VT originating from left ventricle anterior papillary muscles have similar ECG and diagram characteristics that is different from which originating from left anterior fascicle.It is recommended to get the target via transseptalpuncure approach.Ablation target could be clearly positioned by three-dimensional intracardiac ultrasound technology.

Aim To investigate the effect of astragalo-side IV ( ASIV) on myocardial energy metabolism and mitochondrial biosynthesis in myocardial cells of dia-betic rats induced by streptozotocin ( STZ ) . Methods
50 SD rats at 6 weeks of age were assigned to 5 groups,10 for each group:control group, model group, ASIV 10 mg·kg-1 ·d-1 group, ASIV 20 mg·kg-1 ·d-1 group, ASIV 40 mg·kg-1 ·d-1 group. Except the control group,the remaining 40 were used to estab-lish type 1 diabetes model by the tail vein injection of STZ (35 mg·kg-1 ) . At the end of 16 weeks of treat-ment, left ventricular systolic pressure ( LVSP ) , left ventricular diastolic final pressure ( LVEDP ) and left ventricular maximum rising/falling rate ( ± dp/dtmax ) were tested. Pathological section was observed by HE staining. ATP, ADP, AMP levels were detected by ELISA. The expressions of PGC-1α and NRF-1 protein were assessed by Western blot. The expressions of PGC-1α and NRF-1 mRNA were determined by RT-PCR. Results Compared with control group, model group markedly elevated LVEDP and decreased LVSP, ± dp/dtmax , ATP/AMP and ATP/ADP ratio. Com-pared with model group, low-dose ASIV group did not change significantly,middle-dose ASIV group and high-dose ASIV group obviously decreased LVEDP, and im-proved LVSP, ± dp/dtmax , ATP/ADP and ATP/AMP ratio. Meanwhile, the expressions of PGC-1α and NRF-1 protein and mRNA were increased in a dose-de-pendent manner. Conclusion ASIV could promote mitochondrial biosynthesis, improve energy metabolism in myocardial cells of type 1 diabetic rats by PGC-1αand NRF-1 .

OBJECTlVE To investigate the mechanism of verapamiI in the treatment of type 2 Iong QT syndrome(LQT2)using a rabbit Ieft ventricuIar myocardiaI wedge preparation. METHODS E-4031 (0.5 μmoI·L-1 )was used to induce the LQT2 modeI after rabbit Ieft ventricuIar wedge preparations were equiIibrated for 1 h,and verapamiI(0.5,1.0 and 2.5 μmoI·L-1 ,respectiveIy)was perfused in different groups. Data were coIIected for a period of 30 min starting 30 min after adding the respective drug. Transmembrane action potentiaIs of endocardiaI and epicardiaI myocardium were recorded simuItaneous-Iy at a basic cycIe Iength of 2000 ms(S1S1)together with a transmuraI ECG. The effect of verapamiI (0.5,1.0 and 2.5 μmoI·L-1 )on action potentiaI duration at 90% repoIarization(APD90 ),QT intervaI, transmuraI dispersion of repoIarization(TDR)and the deveIopment of earIy afterdepoIarization(EAD) and torsades de pointes(TdP)were evaIuated in the LQT2 myocardiaI wedge modeI. RESULTS E-4031 (0.5 μmoI·L-1 )markedIy proIonged endocardiaI and epicardiaI APD90 and QT intervaI( P﹤0.01),and dramaticaIIy increased TDR(P﹤0.01). Spontaneous or programmed eIectricaI stimuIation-induced EAD and TdP were aIso observed in the modeI. VerapamiI(0.5,1.0 and 2.5 μmoI·L-1 )dose-dependentIy abbreviated endocardiaI and epicardiaI APD90 and QT intervaI(P﹤0.01),significantIy decreased TDR(P﹤0.01),and suppressed EAD and TdP in the LQT2 modeI. Concordant but stronger effects on the eIectro-physioIogicaI properties of the LQT2 modeI were noticed when nifedipine was perfused. CONCLUSlON VerapamiI inhibits TdP in the LQT2 modeI by reducing TDR and suppressing EAD.

10.3969/j.issn.2095-4344.2013.26.013

Objective To explore the effect of psychological nursing on patients with condyloma acuminatum. Methods 324 patients with condyloma acuminatum were randomly divided into the intervention group and the control group with 162 cases in each group.All patients were given carbon dioxide laser therapy,based upon this,the control group was given routine nursing,and the intervention group was additionally given psychological nursing.The anxiety and depression score and the treatment effect were compared between the two groups. Results After one-month treatment,the scores of SAS,SDS in the intervention group declined obviously compared wilt those of pre-treatment and the control group.The cure rate and the recurrce rate in the intervention group were 86.4％ and 13.6％,significantly better than those of the control group. Conclusions Psychological nursing can remit the anxiety and depression emotion of patients with concdylouna acuminatum,improve the cure rare and reduce the recurrence rate of condyloma acuminatum.