Engineering enhanced chimeric antigen receptor-T cell therapy for solid tumors.

The early clinical success and subsequent US Food and Drug Administration approval of chimeric antigen receptor (CAR)-T cell therapy for leukemia and lymphoma affirm that engineered T cells can be a powerful treatment for hematologic malignancies. Yet this success has not been replicated in solid tumors. Numerous challenges emerged from clinical experience and well-controlled preclinical animal models must be met to enable safe and efficacious CAR-T cell therapy in solid tumors. Here, we review recent advances in bioengineering strategies developed to enhance CAR-T cell therapy in solid tumors, focusing on targeted single-gene perturbation, genetic circuits design, cytokine engineering, and interactive biomaterials. These bioengineering approaches present a unique set of tools that synergize with CAR-T cells to overcome obstacles in solid tumors and achieve robust and long-lasting therapeutic efficacy.

Diurnal and seasonal patterns of soil CO2 efflux from the Pichavaram mangroves, India.

The diurnal and seasonal variation of soil carbon dioxide (CO2) flux was measured in the Pichavaram mangrove forest, the Southeast coast of India from February 2016 to October 2016 using an automated soil CO2 flux chamber system. Maximum soil CO2 efflux reached at 14:00 h and minimum at 00:00 h. The surface soil CO2 concentration ranged from 375 to 532 ppm with the mean 405 ± 18 ppm. The daily soil CO2 flux varied from near zero to about 7 µmol m-2 s-1 with a mean value of 2.4 ± 1.3 µmol m-2 s-1. The highest seasonal CO2 efflux from soil was during the summer and premonsoon seasons, whereas low flux values were recorded during the monsoon season. Soil CO2 efflux values were highly correlated with soil temperature. Tidal inundation during monsoon season, extreme drought condition in summer, and unusual precipitation are the major factors controlling the soil CO2 flux.

Hypothesis: selective phosphodiesterase-5 inhibition improves outcome in preeclampsia.

The pathogenesis of preeclampsia stems from aberrant changes at the placental interface. The trophoblastic endovascular invasion of tonic spiral arteries that converts them to passive conduits falters. Uteroplacental insufficiency and fetoplacental hypoxemia result. Secondary maternal oxidative stress and an excessive inflammatory response to pregnancy generate the clinical syndrome of preeclampsia. Current treatment focuses on preventing seizures, controlling hypertension, preserving renal function and delivering the baby. We propose that the pathophysiological changes induced by preeclampsia in the placenta parallel those caused by persistent hypoxemia in the lungs at high altitude or with chronic obstructive pulmonary disease. Unrelenting pulmonary hypoxic vasoconstriction induces pulmonary hypertension and cor pulmonale. Inhalation of nitric oxide and phosphodiesterase-5 inhibitors opposes pulmonary hypoxic vasoconstriction, alleviates pulmonary hypertension and improves systemic oxygenation. Notably nitric oxide donor therapy also counters hypoxemic fetoplacental vasoconstriction, a biological response analogous to pulmonary hypoxic vasoconstriction. Fetal oxygenation and nutrition improve. Placental upstream resistance to umbilical arterial blood flow decreases. Fetal right ventricular impedance falls. Heart failure (cor placentale) is avoided. Emergency preterm delivery can be postponed. Other than low dose aspirin and antioxidants vitamins C and E no available therapy specifically targets the underlying disease profile. We hypothesize that, like nitric oxide donation, pharmacological inhibition of placental phosphodiesterase-5 will also protect the fetus but for a longer time. Biological availability of guanosine 3'5'-cyclic monophosphate is boosted due to slowed hydrolysis. Adenosine 3'5'-cyclic monphosphate levels increase in parallel. Cyclic nucleotide accumulation dilates intact tonic spiral arteries and counters hypoxemic fetoplacental vasoconstriction. Intervillous and intravillous perfusion pick up. Maternal to fetal placental circulatory matching improves. Enhanced placental oxygen uptake alleviates hypoxemic fetal stress. Appropriate fetal nutrition resumes. Cor placentale and severe intrauterine growth restriction are averted. Increased maternal cyclic nucleotide concentrations promote systemic vasodilatation so that blood pressures fall. Preemption of oxidative stress initiated by "consumptive" oxidation of nitric oxide stabilizes the vascular endothelium and corrects coagulopathy. Anti-inflammatory and immunosuppressant adenosine 3'5'-cyclic monphosphate offsets the extreme gestational inflammatory response. Cellular injury and multi-organ damage are prevented. One tablet a day of the new long acting phosphodiesterase-5 inhibitor, tadalafil (half life of 17.5 h) theoretically should allow a preterm pregnancy affected by preeclampsia to continue safely. Selective monitoring of vital organ functions guards against life-threatening maternal complications. Regular biophysical profiling warns the obstetrician of impending fetal compromise. Fetal growth and vital organ maturation can continue. As a result workloads imposed upon neonatal intensivists will lighten. Parental anxiety and concern will be allayed. The cost of treating preeclamptic mothers and their extremely low birth weight infants will decrease. Money saved by midwifery services in poorer states can be used to pay for better prenatal care. Severe preeclampsia/eclampsia will be less common. Maternal and perinatal morbidity and mortality will be reduced. Because the human immunodeficiency virus often infects individuals at a workforce eligible age, the global acquired immunodeficiency syndrome pandemic has already brought many nations to the brink of economic ruin. Potentially productive lives saved for the future will help restore them fiscally.

An evaluation of a new continuous blood pressure monitoring system in critically ill patients.

STUDY OBJECTIVE: To determine if the DxTek monitor, which is a device that measures blood pressure (BP) noninvasively and continuously by means of pulse velocity and wave shapes derived from the pulse oximeter optical plethysmograph and electrocardiogram is as accurate as an oscillometric cuff device when compared with intraarterial BP measurement. DESIGN: Prospective, comparative study. SETTING: University Medical Center. PATIENTS: 28 intensive care unit patients. INTERVENTIONS: Blood pressures were reported every minute by intraarterial catheters and DxTek and every 10 minutes by an oscillometric monitor for 2 to 5 hours. DxTek calibration was performed initially and when specified patient manipulations by caretakers were performed (on average, every 100 minutes). Comparisons with intraarterial pressure included: 1) DxTek calibrated with arterial catheter pressure, 2) DxTek calibrated with oscillometric pressure, and 3) oscillometric pressure. MEASUREMENTS AND MAIN RESULTS: When comparing oscillometric pressure to intraarterial pressure, the averages of the mean differences (bias) were -4.0 mmHg for systolic (SBP) and < 1.5 mmHg for diastolic (DBP) and mean (MAP) pressures. The averages of the standard deviation of the differences (precisions) were 9.6, 6.4, and 6.3 mmHg, respectively. With the DxTek device calibrated to intraarterial pressure, comparison of the DxTek pressure to intraarterial pressure resulted in a bias < OR = 0.5 mmHg for all three pressures and an average precision of 10.1 mmHg for SBP, 6.0 mmHg for DBP, and 6.7 mmHg for MAP. With the DxTek device calibrated to the oscillometric pressure, the DxTek pressure compared to the intraarterial pressure resulted in average biases of -5.1, -0.8, and -2.2 mmHg and average precisions of 11.1, 7.7, and 8.1 mmHg for SBP, DBP, and MAP, respectively. CONCLUSIONS: The DxTek monitor provides continuous, noninvasive BP measurements with an accuracy comparable to oscillometric devices.

A comparison of the placental transfer of ropivacaine versus bupivacaine.

UNLABELLED: This study compares the placental transfer of ropivacaine and bupivacaine using the dual perfused, single cotyledon human placental model. We studied the effects of maternal/fetal protein binding, maternal ropivacaine concentration, and fetal pH on ropivacaine transfer. At a clinically relevant maternal concentration (1 microg/mL), the calculated transfer ratios (local anesthetic percent transfer/antipyrine percent transfer) of ropivacaine (0.82 +/- 0.03) and bupivacaine (0.74 +/- 0.01) were comparable at the completion of the perfusion experiment (120 min). When the perfusates were modified to simulate actual in vivo plasma protein binding values, the maternal-to-fetal transfer of ropivacaine and bupivacaine decreased significantly (P < 0.05) as indicated by transfer ratios of 0.42% +/- 0.07% and 0.40% +/- 0.03%, respectively. No saturation of the transfer process was observed for either drug at the maternal concentrations investigated. The placental transfer of both local anesthetic agents increased significantly as the fetal pH decreased. This investigation shows that ropivacaine and bupivacaine cross the human placenta at a similar rate, despite their differences in lipophilicity and stereochemistry. Placental transfer of both compounds is highly influenced by maternal and fetal protein concentration and the fetal pH. IMPLICATIONS: The placental transfer of ropivacaine was shown to be similar to that of bupivacaine, and is thus highly influenced by the degree of maternal and fetal protein binding and fetal pH.

Chromogenic agar for rapid presumptive identification of yeast species:--a preliminary report.

A chromogenic medium for the rapid presumptive identification of yeasts was devised and studied. The medium was found to be effective in differentiating the yeast species studied on the basis of colony colour. With further modification the medium can be used as a primary isolation medium.

Intrathoracic complications of acute pancreatitis.

Acute pancreatitis has an incidence of approximately 50 cases per million of the United Kingdom population and a mortality of 10-18%. Intrathoracic complications have been implicated as the major factor in 22-29% and a contributing factor in a further 29-39% of all deaths. Sixty per cent of deaths occur in the first week of hospital admission and in these the pleuropulmonary complication rate is 94%. In the survivors there is little residual lung damage and the recovery of the pulmonary function is invariably complete. Knowledge of the pleuropulmonary complications of acute pancreatitis may aid with the identification of high risk groups so that supportive measures (including mechanical ventilation) can be implemented early in the course of the illness. This article reviews the major intrathoracic complications of acute pancreatitis (Fig. 1) under the broad headings of: 1. pleural effusion 2. acute pulmonary dysfunction (a) hypoxaemia without pulmonary infiltrates (b) hypoxaemia with pulmonary infiltrates (including the adult respiratory distress syndrome; ARDS).

Evaluation of blood loss during suction termination of pregnancy: ketamine compared with methohexitone.

Blood loss during suction termination of pregnancy was estimated in patients anaesthetised with intravenous ketamine (n = 25) and compared with those anaesthetised with intravenous methohexitone (n = 25). Both groups received midazolam 0.15 mg/kg intravenously 3 min prior to induction of anaesthesia. No statistically significant difference was found in blood loss between the two groups (P = 0.66). There was no incidence of dreaming or psychomotor disturbances with ketamine in our study.

PIP: This study compared blood loss associated with suction termination of 1st-trimester pregnancy in 25 women anesthetized with intravenous ketamine and 25 women who received methohexitone anesthesia. Both groups were given 0.15 mg/kg of midazolam intravenously 3 minutes before anesthesia induction. There was no significant difference in blood loss between the 2 groups. The mean blood loss was 85.7 ml in the methohexitone group and 79.5 ml in the ketamine group. The unpleasant dreams, delirium, and psychomotor disturbances previously reported to be associated with use of ketamine were not observed in this study, presumably because of the administration of midazolam. However, 12 of the women in the ketamine group experienced postoperative nausea and 6 of them vomited, compared with only 1 in the methohexitone group. Although there was no correlation between anesthesia and blood loss, blood loss was significantly greater with increasing gestational age. It is concluded that ketamine does not offer any advantage over methoheitone in terms of blood loss during suction abortion. If ketamine is to be used for this procedure, routine use of an antiemetic should be considered to counteract the high incidence of nausea and vomiting.

Beta-2-adrenoceptor agonists as inhibitors of lung vascular permeability to radiolabelled transferrin in the adult respiratory distress syndrome in man.

Increased lung vascular permeability leading to increased plasma protein extravasation and accumulation (PPA) is a characteristic feature of acute lung injury. Using a previously described technique, PPA was monitored in the lungs of patients with the adult respiratory distress syndrome (ARDS)--an extreme example of acute lung injury in man. An external radiation probe detector was used to monitor the pulmonary accumulation of the plasma protein transferrin radiolabelled in-vivo with 113mIn. Ten patients with ARDS exhibiting increased PPA indices (greater than 1.0 x 10(-3)/min) were given an intravenous infusion of terbutaline (7 micrograms/kg) over 30 min. Of the four patients in whom the post-drug PPA indices remained within the ARDS range, none survived, whilst five of the six patients in whom the post-drug PPA indices were reduced to below 1.0 x 10(-3)/min survived. PPA indices prior to the administration of terbutaline were not significantly different between the survivor (n = 5) and non-survivor (n = 5) groups. There was a significant decrease in the PPA indices following terbutaline in survivors (p less than 0.01) but not in non-survivors. Thus beta-2-agonists in therapeutic doses can inhibit increased lung vascular permeability in man. These findings may have prognostic and therapeutic implications for beta-2-agonists in ARDS.

Anesthesia for termination of pregnancy: midazolam compared with methohexital.

Clinical effects of intermittent intravenous administration of midazolam were compared with those of methohexital in two groups of ten premedicated patients each undergoing suction termination of pregnancy under general anesthesia. Both groups received intravenous fentanyl (1 microgram/kg) 5 min prior to administration of the induction agent. No significant difference was found between the two groups in induction time and quality of anesthesia. The recovery time was significantly (17 min) longer in patients who received midazolam (P less than 0.0001).

PIP: This study compared the clinical effects of midazolam with methohexital when these agents were administered intravenously by intermittent injection in 20 outpatients undergoing suction termination of pregnancy. Both groups were premedicated with intramuscular papaveretum and scopolamine 1 hour before the procedure and received fentanyl 5 minutes before the induction of anesthesia. The mean induction time between completion of administration of the intravenous anesthetic agent and the loss of eyelash reflex was 36.7 + or - 15.2 seconds among the 10 women who received midazolam and 41 + or - 34.5 seconds among the 10 women in the methohexital group; this difference was not statistically significant. The group receiving midazolam was given an induction dose of 8.8 + or - 1.5 mg and a total dose of 17.8 + or - 3.8 mg. The methohexital group received an induction dose of 58.5 + or - 9.1 mg and a total dose of 127.5 + or - 22.8 mg. Recovery (defined as the interval between discontinuation of nitrous oxide and the time when the patient responded purposively to oral commands) took 20.1 + or - 8.4 minutes in the midazolam group and 3.2 + or - 2.4 minutes in the methohexital group, a difference that was highly significant. The mean scores for the overall quality of anesthesia were not significantly different. No serious cardiorespiratory complications were noted in either group. This study shows that midazolam compares favorably with methohexital in terms of induction characteristics and the overall quality of anesthesia; however, the recovery time is significantly longer (17 minutes) with midazolam.