[Efficacy and safety of neoadjuvant chemotherapy combined with PD-1 antibody for esophageal squamous cell carcinoma in the real world].

Objective: To evaluate the efficacy and safety of neoadjuvant chemotherapy combined with programmed death-1 (PD-1) antibody in operable, borderline or potentially resectable locally advanced esophageal squamous cell carcinoma(ESCC) in the real world. Methods: The study retrospectively analyzed 28 patients with operable or potentially resectable locally advanced ESCC patients treated with preoperative chemotherapy combined with PD-1 inhibitor in Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School from April 2020 to March 2021. According to the clinical TNM staging system of the 8th edition of the American Joint Committee on Cancer, there were 1, 15, 10, 1 and 1 case of stage Ⅱ, Ⅲ, ⅣA, ⅣB and unknown stage respectively. The treatment was two cycle of dual drug chemotherapy regimen including taxane plus platinum or fluorouracil combined with PD-1 antibody followed by tumor response assessment and surgery if the patient was eligible for resection. Results: Of the 28 patients, 1, 2, 3 and 4 cycles of chemotherapy combined with PD-1 antibody treatment completed in 1, 21, 5, and 1 patient, respectively. Objective response rate (ORR) was 71.4% (20/28), and disease control rate (DCR) was 100% (28/28). The incidence of adverse events exceeding grade 3 levels was 21.4% (6/28), including 3 neutropenia, 1 leukopenia, 1 thrombocytopenia and 1 immune hepatitis. There was no treatment-related death. Of the 23 patients underwent surgery, R0 resection rate was 87.0% (20/23), 13 patients had down staged to the T1-2N0M0 I stage, the pCR rate was 17.3% (4/23), and the pCR rate of primary tumor was 21.7% (5/23). Four patients received definitive chemoradiotherapy. One patient rejected surgery and other treatment after achieved PR response. Conclusion: Neoadjuvant chemotherapy combined PD-1 inhibitor is safe and has high efficacy in operable, borderline or potentially resectable locally advanced ESCC, and it is a promising regimen.

[Effects and mechanism of digoxin on atrium electrical remodeling and susceptibility of atrial fibrillation in aged rabbits].

Objective: To investigate the effects and mechanism of digoxin on atrium electrical remodeling and susceptibility of atrial fibrillation (AF) in aged rabbits. Methods: Twenty aged male New Zealand rabbits were divided into aged group and aged plus digoxin group (n=10 each). Electrical parameters including heart rate (HR), RR and QT interval, ST segment and P wave dispersion from normal Ⅱ electrocardiogram, and the maximum upstroke velocity (Max(dv/dt)), plateau potential (plateau P), action potential duration of 10%, 20% and 90% (APD(10), APD(20), APD(90)) from recording of monophasic action potential (MAP), as well as atrial effective refractory period (AERP(200)) and dispersion (dERP(200)) with 200 ms of basic cycle length (BCL), and frequency self adaptation of AERP with 300 ms and 150 ms of BCLs (fERP) were recorded and compared between the 2 groups. BCLs and inducibility of AF post programmed electrical stimulation and Burst-pacing in left atrium tissue of rabbits in vivo were also analyzed. The L-type calcium current (I(Ca-L)) in 2 groups were recorded via whole-cell patch clamp technique, and the fluorescence intensity of intracellular free Ca(2+) was detected with Flup-3/AM loading by the laser scanning confocal microscope in enzymatically dissociated single rabbit atrial myocytes. Results: Compared with aged group, the heart rate was faster, RR and QT interval were obvious shorter, ST segment was raised and P wave dispersion was significantly increased in aged plus digoxin group (all P<0.05). Moreover, compared with aged group, the Max(dv/dt) and plateau P were obviously increased, APD(10) and APD(20) were significantly prolongated, and APD(9)0 was significantly shorter in aged plus digoxin group (all P<0.01). Otherwise, the fERP was markedly increased (0.81±0.15 vs. 0.67±0.05), and the induced rate of AF was obviously higher in aged plus digoxin group than in aged group (6/8 vs. 4/9) (all P<0.01). With voltage clamp model, digoxin significantly increased I(Ca-L) of atrial myocytes of aged rabbits, When command potential was 10 mV, the current densities of I(Ca-L) were significantly higher in digoxin group than that in aged group ((15.45±2.38) pA/pF vs. (7.03±1.69) pA/pF, P<0.01). Otherwise, the I-V curve of I(Ca-L) was downward shifted of all I-V curves in digoxin perfused aged atrial cells of rabbits. Moreover, the fluorescence intensities of intracellular free Ca(2+) was significantly higher in aged plus digoxin group than in aged group ((1 748±173) µmol/L vs. (478.13±87.63) µmol/L, P<0.01). Conclusion: Digoxin could aggravate the atrial electrical remodeling in atrium of aged rabbits, facilitate susceptibility of atrial fibrillation in aged rabbit, increased current density of I(Ca-L) and concentration of intracellular free Ca(2+), followed Ca(2+) overload and oscillations might be part of the underlying mechanisms.

Use of RNA interference to modulate liver adenoma development in a murine model transgenic for hepatitis B virus.

Chronic hepatitis B virus (HBV) infection is closely related to the development of severe liver complications, including hepatocellular carcinoma. In previous studies, we reported that in vivo long-term HBV suppression in transgenic mice can be achieved without apparent toxicity by short hairpin RNA sequentially delivered using adeno-associated viral (AAV) vectors of different serotypes. Our goal herein was to address the clinical utility of this delivery system and, in particular, to determine whether RNA interference (RNAi) and its ability to induce long-term HBV suppression will modulate the development of HBV-associated liver pathology. As a model system, we used a unique HBV transgenic mouse model, containing a 1.3 times over length of the HBV genome, on the ICR mouse background. These transgenic mice produce high serum HBV titers comparable with human chronic HBV patients, and, importantly, manifest characteristic HBV-associated pathology, including progressive hepatocellular injury and the development of hepatocellular adenoma. Using this system, we injected animals with AAV vectors expressing either HBV-specific or a control luciferase-specific short hairpin RNA and followed animals for a total of 18 months. We report herein that AAV-mediated RNAi therapy profoundly inhibits HBV replication and gene expression, with a significant reduction in hepatic regeneration, liver enzymes and, importantly, the appearance of liver adenomas. Indeed, the therapeutic effect of RNAi correlated with the reduction in HBV titers. Our data demonstrate that appropriately designed RNAi therapy has the potential to prevent formation of HBV-associated hepatocellular adenoma.

Risk factors for incident diabetes mellitus among HIV-infected patients receiving combination antiretroviral therapy in Taiwan: a case-control study.

OBJECTIVES: Recent studies suggest that patients with HIV infection are at increased risk for incident diabetes mellitus (DM). We investigated the incidence and risk factors of DM among HIV-infected patients receiving combination antiretroviral therapy (CART) in Taiwan. METHODS: Incident cases of DM were identified among HIV-infected patients at the National Taiwan University Hospital between 1993 and 2006. A retrospective case-control study was conducted after matching cases with controls for sex, age at HIV diagnosis, year of HIV diagnosis, mode of HIV transmission and baseline CD4 lymphocyte count. A multivariate analysis was performed to identify risk factors for incident DM among HIV-infected patients. RESULTS: In 824 HIV-infected patients eligible for analysis, 50 cases of incident DM were diagnosed, resulting in an incidence of 13.1 cases per 1000 person-years of follow-up. In total, 100 matched controls were identified. Risk factors for incident DM were a family history of DM [odds ratio (OR) 2.656; 95% confidence interval (CI) 1.209-5.834], exposure to zidovudine (OR 3.168; 95% CI 1.159-8.661) and current use of protease inhibitors (OR 2.528; 95% CI 1.186-5.389). CONCLUSIONS: Incident DM was associated with a family history of DM, exposure to zidovudine and current use of protease inhibitors in HIV-infected patients receiving CART in Taiwan.

Structure-activity relationship (SAR) studies of synthetic glycogen synthase kinase-3ß inhibitors: A critical review.

Glycogen Synthase Kinase-3 (GSK-3) is a constitutively dynamic, omnipresent serine/threonine protein kinase regularly called as a "multitasking kinase" due to its pliable function in diverse signaling pathways. It exists in two isoforms i.e., GSK-3α and GSK-3ß. Inhibition of GSK-3 may be useful in curing various diseases such as Alzheimer's disease, type II diabetes, mood disorders, cancers, chronic inflammatory agents, stroke, bipolar disorders and so on, but the approach poses significant challenges. Lithium was the first GSK-3ß inhibitor to be used for therapeutic outcome and has been effectively used for many years. In recent years, a large number of structurally diverse potent GSK-3ß inhibitors are reported. The present review focuses on the recent developments in the area of medicinal chemistry to explore the diverse chemical structures of potent GSK-3ß inhibitors and also describes its structure-activity relationships (SAR) and molecular binding interactions of favorable applicability in various diseases.

Current patterns of neonatal morbidity and mortality in infants of diabetic mothers.

Recent advances in antepartum fetal evaluation have contributed to a marked reduction in fetal deaths in pregnancies complicated by overt diabetes mellitus. To determine the effect of these changes on neonatal morbidity and mortality, a retrospective analysis of complications in 322 infants of diabetic mothers (IDM) in White classes B--R was undertaken. The majority (89 per cent) of the IDM were delivered at term with a mean gestational age of 38 weeks. Neonatal morbidity correlated significantly with gestational age, occurring in 80 per cent of the preterm and 40 per cent of the term infants. The overall incidence of complications was: hyperbilirubinemia 37 per cent, hypoglycemia 31 per cent, hypocalcemia 13 per cent, polycythemia 8 per cent, and necrotizing enterocolitis 2 per cent. Respiratory distress syndrome (RDS) occurred in 9 per cent and congenital malformations in 6 per cent of the infants. Nine infants died, and four of these deaths were due to anomalies. These data indicate that (1) a reduction in fetal mortality has been accompanied by a reduction in neonatal mortality; (2) neonatal morbidity has been decreased but remains significant in the IDM; and (3) congenital anomalies have replaced RDS as a major cause of neonatal death for the IDM.

Use of fetal ultrasound to select metabolic therapy for pregnancies complicated by mild gestational diabetes.

OBJECTIVE: To determine whether fetal ultrasound early in the third trimester can identify Latina with mild gestational diabetes mellitus (GDM) whose fetuses are at risk for macrosomia and, if so, whether maternal insulin therapy can reduce that risk. RESEARCH DESIGN AND METHODS: Study subjects included 303 consecutive women with GDM and a fasting serum glucose level < 5.8 mM on diet therapy who had a fetal ultrasound between 29 and 33 weeks gestation. Of the women, 98 (32%) had a fetal AC > or = 75th percentile for gestational age, and 59 women completed a randomized trial of diet therapy (n = 29) or diet plus twice daily insulin (n = 30). Maternal nutrient levels were assessed by meal tolerance testing (MTT) before and during therapy and by capillary glucose monitoring four to seven times a day. Birth weights corrected for gestational age and neonatal glycemia and skin folds were the primary outcome variables compared between treatment groups. RESULTS: Diet and diet-plus-insulin groups were well matched for maternal age, prepregnancy relative weight, weight gain during pregnancy, and glycemia at entry. Insulin therapy reduced maternal capillary (P < 0.005) and MTT (P < 0.001) glucose levels and prevented a diet-associated rise in MTT triglyceride levels (P < 0.002). Gestational age at delivery was similar in insulin- and diet-treated groups (39.6 +/- 0.2 vs. 39.5 +/- 0.2 weeks). Birth weights (3,647 +/- 67 vs. 3,878 +/- 84 g; P < 0.02), the prevalence of large-for-gestational age infants (13 vs. 45%, P < 0.02), and neonatal skin-fold measurements at three sites (P < 0.005) were reduced in the insulin-treated group. Rates of transient neonatal hypoglycemia were low in both treatment groups (14 and 18%, respectively) and did not differ significantly between groups. CONCLUSIONS: Fetal ultrasound early in the third trimester identified women with mild GDM whose infants were at high risk for fetal macrosomia in the absence of standard glycemic criteria for insulin therapy. Insulin treatment reduced the macrosomia, indicating that fetal ultrasound can be used to guide metabolic therapy in pregnancies complicated by mild GDM.

PHRF1 promotes genome integrity by modulating non-homologous end-joining.

Methylated histone readers are critical for chromatin dynamics, transcription, and DNA repair. Human PHRF1 contains a plant homeodomain (PHD) that recognizes methylated histones and a RING domain, which ubiquitinates substrates. A recent study reveals that PHRF1 is a tumor suppressor that promotes TGF-ß cytostatic signaling through TGIF ubiquitination. Also, PHRF1 is a putative phosphorylation substrate of ataxia telangiectasia-mutated/ataxia telangiectasia and Rad3-related kinases; however, the role of PHRF1 in DNA damage response is unclear. Here we report a novel function of PHRF1 in modulating non-homologous end-joining (NHEJ). PHRF1 quickly localizes to DNA damage lesions upon genotoxic insults. Ablation of PHRF1 decreases the efficiency of plasmid-based end-joining, whereas PHRF1 overexpression leads to an elevated NHEJ in H1299 reporter cells. Immunoprecipitation and peptide pull-down assays verify that PHRF1 constitutively binds to di- and trimethylated histone H3 lysine 36 (H3K36) (H3K36me2 and H3K36me3) via its PHD domain. Substitution of S915DT917E to ADAE in PHRF1 decreases its affinity for NBS1. Both PHD domain and SDTE motif are required for its NHEJ-promoting activity. Furthermore, PHRF1 mediates PARP1 polyubiquitination for proteasomal degradation. These results suggest that PHRF1 may combine with H3K36 methylation and NBS1 to promote NHEJ and stabilize genomic integrity upon DNA damage insults.

Unexpectedly high prevalence of Treponema pallidum infection in the oral cavity of human immunodeficiency virus-infected patients with early syphilis who had engaged in unprotected sex practices.

Between 2010 and 2014, we obtained swab specimens to detect Treponema pallidum, with PCR assays, from the oral cavities of 240 patients with 267 episodes of syphilis who reported engaging in unprotected sex practices. The detected treponemal DNA was subjected to genotyping. All of the syphilis cases occurred in men who have sex with men (MSM), and 242 (90.6%) occurred in human immunodeficiency virus-infected patients. The stages of syphilis included 38 cases (14.2%) of primary syphilis of the genital region, 76 (28.5%) of secondary syphilis, 21 (7.9%) of primary and secondary syphilis, 125 (46.8%) of early latent syphilis, and seven (2.6%) others. Concurrent oral ulcers were identified in 22 cases (8.2%). Treponemal DNA was identified from the swabs of 113 patients (42.2%), including 15 (68.2%) with oral ulcers. The most common genotype of T. pallidum was 14f/f. The presence of oral ulcers was associated with identification of T. pallidum in the swab specimens (15/22 (68.2%) vs. 98/245 (40.0%)) (p = 0.01). In multivariate analysis, secondary syphilis (adjusted OR 6.79; 95% CI 1.97-23.28) and rapid plasma reagin (RPR) titres of ≥1: 32 (adjusted OR 2.23; 95% CI 1.02-4.89) were independently associated with the presence of treponemal DNA in patients without oral ulcers. We conclude that detection of treponemal DNA in the oral cavity with PCR assays is not uncommon in MSM, most of whom reported having unprotected oral sex. Although the presence of oral ulcers is significantly associated with detection of treponemal DNA, treponemal DNA is more likely to be identified in patients without oral ulcers who present with secondary syphilis and RPR titres of ≥1: 32.

Plasma amino acid concentrations in premature infants: effect of sampling site.

Amino acid concentrations in plasma obtained from infants by heel puncture differ from those in venous plasma primarily because of skin contamination but data from the two sites might agree more closely in premature infants because of their poorly developed sweat glands. To evaluate the importance of sampling site, amino acids were analyzed by a sensitive high-performance liquid chromatographic method in plasma obtained both by heel puncture and venipuncture in 14 premature infants. Histidine, tryptophan, alanine, aspartic acid, glycine, and serine were higher in capillary plasma. Tryptophan and glycine levels in capillary plasma correlated strongly with those in venous plasma. An additional wash with soap and water done in five infants did not eradicate the differences. Thus the lack of agreement between data from the two sites may be due to factors other than contamination.

Effect of phototherapy on nitrogen and electrolyte levels and water balance in jaundiced preterm infants.

Twenty-four-hour metabolic balance studies were performed in ten jaundiced preterm infants, five light-treated (phototherapy) and five controls. Each of the light-treated infants was studied twice, once during phototherapy (period I) and once 48 hours after phototherapy (period II). Control infants were similarly studied during the corresponding days. Compared to period II and control infants, during period I the light-treated infants had less weight gain. Intestinal transit time was decreased by 50%. Fecal excretion of nitrogen, sodium, and potassium was increased. Stool water loss was increased twofold to threefold with a decrease in water balance. Unmeasured water loss was increased. These studies underscore the need for careful attention to fluid and caloric supplementation during phototherapy.

Cardiovascular changes in preterm infants nursed under radiant warmers.

Radiant heat is known to increase insensible water loss and, to a certain extent, oxygen consumption. Little is known about its cardiovascular effects. We measured cardiac output, stroke volume, heart rate, and lower limb and skin blood flow in 20 preterm newborn infants nursed in an incubator and under a radiant warmer at an abdominal skin temperature of 36.5 degrees C. Mean (+/- SEM) birth weight was 1.57 (0.06) kg, gestational age 31.7 (0.4) weeks, and weight at examination 1.69 (0.02) kg; median postnatal age was 15 days. Skin and limb blood flow measurements increased by 44% to 55% with radiant heat (P less than .001 and P less than .01, respectively). Cardiac output increased by 5.4% (P less than .02) under the radiant warmer secondary to a small but significant (P less than .05) increase in heart rate. The changes in cardiac output during radiant heat administration are comparable to those reported for oxygen consumption.

Visual following and pattern discrimination of face-like stimuli by newborn infants.

Forty newborn infants, median age 9 minutes, turned their eyes and heads to follow a series of moving stimuli. Responsiveness was significantly greater to a proper face pattern than to either of two scrambled versions of the same stimulus or to a blank. The demonstration of such consistent response differences suggests that visual discriminations are being made at this early age. These results imply that organized visual perception is an unlearned capacity of the human organism. The preference for the proper face stimulus by infants who had not seen a real face prior to testing suggests that an unlearned or "evolved" responsiveness to faces may be present in human neonates.

Cardiac output changes in newborns with hyperbilirubinemia treated with phototherapy.

Phototherapy is known to increase peripheral blood flow in neonates, but information on the associated cardiovascular effects is not available. Using pulsed Doppler echocardiography we evaluated cardiac output and stroke volume in 12 preterm and 13 term neonates during and after phototherapy. We concomitantly measured arterial limb blood flow by strain gauge plethysmography and skin blood flow by photoplethysmography. Cardiac output decreased by 6% due to reduced stroke volume during phototherapy, whereas total limb blood flow and skin blood flow increased by 38% and 41%, respectively. Peripheral blood flow increments tended to be higher in the preterm than in the term infants. The reduced stroke volume during phototherapy may be an expression of reduced activity of the newborn during phototherapy. For healthy neonates the reduction in cardiac output is minimal, but for sick infants with reduced cardiac output, this reduction may further aggravate the decrease in tissue perfusion.

Pulsed Doppler determinations of cardiac output in neonates: normal standards for clinical use.

Noninvasive monitoring of cardiac output can greatly facilitate the clinical assessment and management of neonates with cardiovascular compromise. To assess normal values of cardiac output in neonates, mean blood flow velocity was measured in the ascending aorta from a suprasternal approach using a range-gated, pulsed Doppler velocity meter, and aortic root diameter was determined from an M-mode echocardiogram. These techniques were combined, and cardiac output was evaluated in 59 healthy premature and 62 term newborn infants during the first week of life. Birth weights ranged from 780 g to 4,740 g and gestational age from 27 to 42 weeks. Cardiac output values increased linearly with advancing birth weight (r = +.94, P less than 0.001) and gestational age (r = +.95, P less than .001). Mean cardiac output values (+/- SD) per kilogram of body weight were 249 +/- 34 mL/min/kg and decreased with advancing birth weight: less than 1,500 g = 265 +/- 32 mL/min/kg; 1,500 to 2,500 g = 253 +/- 34 mL/min/kg; and greater than 2,500 g = 241 +/- 33 mL/min/kg. For clinical use, 325 mL/min/kg and 200 mL/min/kg can be used as upper and lower limits of normal, respectively. Doppler cardiac output estimates compared favorably with studies using invasive techniques.

Colloid osmotic pressure in newborn infants: variations with birth weight, gestational age, total serum solids, and mean arterial pressure.

Colloid osmotic pressure (COP) of blood was measured directly at birth with the Wescor membrane colloid osmometer (model 4100) in 91 appropriately grown, 11 large, and nine small for gestational age "well" newborn infants. COP correlated directly with birth weight (r = .726, P less than .00001) and gestational age (r = .753, P less than .00001). COP values for small for gestational age (SGA) and large for gestational age (LGA) infants were found to fall within the 95% prediction interval with regard to birth weight and gestational age for appropriate for gestational age (AGA) infants. Simultaneous measurements of COP, total serum solids, and central arterial mean blood pressure were made. The results showed that COP correlated directly with total serum solids (r = .89, P less than .0001) and mean arterial blood pressure (r = .660, P less than .001). Among the factors evaluated, total serum solids was the best predictor of COP.

Aqueous humor pilocarpine and timolol levels after instillation of the single drug or in combination.

Aqueous humor levels of pilocarpine and timolol in rabbits after administration of either 2% pilocarpine or 0.5% timolol in single-drug solutions were compared with the concentrations found after instillation of a fixed combination of 0.5% timolol and 2% pilocarpine drops. Time intervals considered were 15 min, 30 min, 1 hr, 4 hr, and 8 hr after application. Drug concentrations were analyzed in individual aqueous samples by high-performance liquid chromatography. No statistically significant differences in either pilocarpine or timolol concentrations in aqueous humor were found at any time tested between the single-drug preparations and the combination.

A comparison of rat brain amino acid and monoamine content in diazepam withdrawal and after exposure to a phobic stimulus.

1. The content of amino acids (taurine, glycine, glutamic acid, gamma-aminobutyric acid (GABA) and aspartic acid) and monoamines (5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and noradrenaline) in homogenates of rat cortical and hippocampal tissue were measured by high performance liquid chromatography (h.p.l.c.) with fluorescent and electrochemical detection respectively, after two anxiogenic treatments: exposure to a phobic stimulus (cat odour) and withdrawal from chronic diazepam treatment. 2. In neither of the two anxiogenic situations was there a significant change in any amino acid content, in either brain area. 3. In the group withdrawn from chronic diazepam, cortical 5-HT and 5-HIAA levels and hippocampal 5-HT levels were significantly increased. Noradrenaline content was significantly decreased in the hippocampus. 4. The changes in 5-HT and 5-HIAA levels following cat odour exposure were area-specific in that they decreased in the hippocampus, but increased in the cortex. 5. Following cat odour exposure, noradrenaline levels appeared not to change in either area studied. However during exposure to cat odour, it was found that half the animals avoided the odour source and half were indifferent. The animals showing marked avoidance had significantly higher cortical noradrenaline content and this was significantly different from control, whereas hippocampal noradrenaline levels were not dependent upon the differences in avoidance of the odour source. 6. The results show clearly different neurochemical changes in the rat following exposure to a phobic stimulus and withdrawal from diazepam. It is hoped comparative studies such as this will enable better understanding of anxiety states in the rat which could parallel the different classes of anxiety recognised in the clinic

Peripartum colloid osmotic pressures: correlation with serum proteins.

Colloid osmotic pressure is a principal regulator of capillary fluid exchange. Alterations in colloid osmotic pressure in preeclamptic patients, as well as significant peripartum changes in colloid osmotic pressure in normotensive patients, are reported. In a study of 72 normotensive and preeclamptic patients, peripartum colloid osmotic pressure, serum albumin, and total serum protein were compared. Both groups exhibited significantly lower colloid osmotic pressure in the postpartum period than that measured antepartum. The mean antepartum colloid osmotic pressure in preeclamptic patients was significantly lower than in normotensive subjects. Regression equations were calculated [colloid osmotic pressure = 5.21 (total serum protein) -11.4 (r2 = 0.851)] and [colloid osmotic pressure = 8.1 (serum albumin) -8.2 (r2 = 0.891)]. Within the physiologic ranges most commonly reported for normotensive and preeclamptic patients, the use of these equations allowed calculation of colloid osmotic pressure to within 10% of measured values in 75 and 80% of the cases, respectively. Where direct measurement of colloid osmotic pressure is not readily available, calculated values may be helpful in patient management.