AC Electrothermal Effect Promotes Enhanced Solute Mixing in a Wavy Microchannel.

For liquids used in biological applications, a smaller diffusion coefficient results in a longer mixing time. We discuss, in this endeavor, the promising potential of the AC electrothermal (ACET) effect toward modulating enhanced mixing of electrolytic liquids with higher convective strength in a novel wavy micromixer. To this end, we develop a modeling framework and numerically solve the pertinent transport equations in a three-dimensional (3D) configuration numerically. By benchmarking the developed modeling framework with the experimental results available in this paradigm, we aptly demonstrate the maximum temperature rise, flow topology, species concentration field, and mixing efficiency in the proposed configuration for a set of parameters pertinent to this analysis. We find that the maximum temperature increase in the wavy micromixer, owing to the electrothermal effect, is less than 10 K even for the higher strength of the applied voltage, implying nondegradation of biological substances within the liquid sample. We report that the formation of significant lateral flow closer to the electrodes leads to a highly three-dimensional ACET flow field, which has a significant impact on the mixing efficiency for the range of diffusive Peclet numbers considered. We also report that the wave amplitude of the mixer, when intervening with the diffusive Peclet number, strongly impacts the mixing efficiency. As witnessed in this endeavor, for the smaller diffusive Peclet number, the mixing efficiency increases with amplitude, while the effect becomes the opposite for the higher Peclet number. The results of this study seem to provide an adequate basis for the design of a novel micromixer intended for enhanced solute mixing in realistic microfluidic applications.

Salinity Gradient-Induced Power Generation in Nanochannels: The Role of pH-Sensitive Polyelectrolyte Layers.

By varying the pH values (pHR) and types of salt solution, we investigate the salinity gradient-induced electrical and mechanical flow energies inside a reservoir-connected charged nanochannel with a grafted pH-sensitive polyelectrolyte layer (PEL) on the inner surfaces. The aqueous solutions of KCl, LiCl, BaCl2, BeCl2, AlCl3, and Co(en)3Cl3 salts are used as the working fluid in the current investigation. We examine the associated ionic transport and flow field, aiming to understand the underlying physics behind the generation of electrical and hydraulic energy through alterations in pHR and types of salt solution. Our results reveal that the PEL space charge density decreases with increasing pHR at lower values, while it remains almost insensitive to higher pHR values. The electrical conductance and maximum pore power of the Co(en)3Cl3 solution are significantly higher compared to salts with monovalent and divalent cations. Furthermore, the magnitude of these two parameters decreases with lower pHR and becomes insensitive to higher pHR values. The results illustrate that the maximum electrical energy conversion efficiency enhances with pHR, reaching its highest level for the Co(en)3Cl3 solution. We expect that the findings of the current work will have a significant bearing on the design and development of a state-of-the-art salinity gradient-based energy convertor as a potential candidate for renewable energy sources.

Actionable spontaneous antibody responses antagonize malignant progression in ovarian carcinoma.

OBJECTIVE: To demonstrate that shared antibody responses in endometriosis and endometriosis-associated ovarian cancer spontaneously antagonize malignant progression and can be leveraged to develop future immunotherapies. METHODS: B cells from cyopreserved clear cell ovarian carcinoma (CCC, n = 2), endometrioid ovarian carcinoma (EC, n = 2), and endometriomas (n = 2) were isolated, activated, and EBV-immortalized. Antibodies were purified from B cell supernatants and used for screening arrays containing most of the human proteome. Targets were prioritized based on accessibility (transmembrane or secreted proteins), expression in endometriosis and cancer, and concurrent IgA and IgG responses. We focused on antibodies targeting tumor-promoting syndecan binding protein (SDCBP) to demonstrate anti-tumor activity. Immunoblots and qPCR were performed to assess SDCBP expression in ovarian cancer and endometriosis cell lines and tumor samples. Recombinant IgG4 was generated using the variable heavy and light chains of dominant B cell receptors (BCRs) reacting against the extracellular domain of SDCBP, and used in in vivo studies in human CCC- and high-grade serous ovarian carcinoma (HGSOC)-bearing immunodeficient mice. RESULTS: Nine accessible proteins detected by both IgA and IgG were identified in all samples - including SDCBP, which is expressed in ovarian carcinomas of multiple histologies. Administration of α-SDCBP IgG4 in OVCAR3 (HGSOC), TOV21G and RMG-I (CCC) tumor-bearing mice significantly decreased tumor volume compared to control irrelevant IgG4. CONCLUSIONS: Spontaneous antibody responses exert suboptimal but measurable immune pressure against malignant progression in ovarian carcinomas. Using tumor-derived antibodies for developing novel immunotherapeutics warrants further investigation.

Vortex-assisted electroosmotic mixing of Carreau fluid in a microchannel.

Pertaining to the mixing of the non-Newtonian Carreau fluid under electrokinetic actuation inside a plane microchannel, we propose a new design of micromixer that involves inserting a two-part cylinder bearing zeta potential of the same sign but different magnitude in the upstream and downstream directions. We numerically solve the transport equations to predict the underlying mixing characteristics. We demonstrate that a substantial momentum difference between the microchannel's plane wall and cylinder leads to the development of a vortex in the flow pathway, which in turn, enhances mixing substantially. As shown, for a fluid having a highly shear-thinning nature, the vortex-assisted convection mixing strength increases with diffusivity of the candidate fluids. Moreover, it is shown that for the higher shear-thinning nature of the candidate fluid, an increase in cylinder radius enhances mixing efficiency and flow rate simultaneously, resulting in a "quick and efficient" mixing condition. Additionally, the fluid rheology significantly alters the kinetics of shear-induced binary aggregation. Our findings show that the shear-induced aggregation characteristic time sharply increases with increasing shear-thinning behavior of the fluid.

Influence of viscoelectric effect on diffusioosmotic transport in nanochannel.

We have investigated the role of viscoelectric effect on diffusioosmotic flow (DOF) through a nanochannel connected with two reservoirs. The transport equations governing the flow dynamics are solved numerically using the finite element technique. We have extensively analyzed the variation of induced field due to electric double layer (EDL) phenomenon, relative viscosity as modulated by the viscoelectric effect as well as reservoir's concentration difference, and their eventual impact on the underlying flow characteristics. It is revealed that the induced electric field in the EDL enhances fluid viscosity substantially near the charged wall at a higher concentration. We have shown that neglecting viscoelectric effect in the paradigm of diffusioosmotic transport overestimates the net throughput, particularly at a higher concentration difference. Furthermore, we show that pertaining to chemiosmosis dominated regime, the average flow velocity modifies with the increase in concentration difference up to a critical value. In comparison, the rise in the strength of resistive electroosmotic actuation by the accumulation of anions in the upstream reservoir reduces the average flow velocity at a higher concentration difference. We have reported a reduction in critical concentration with the increase in viscoelectric effect. The inferences of this analysis are deemed pertinent to reveal the bearing of viscoelectric effect as a flow control mechanism pertaining to DOF at nanoscale.

Olfactory Receptor OR2H1 Is an Effective Target for CAR T Cells in Human Epithelial Tumors.

Although chimeric antigen receptor (CAR)-expressing T cells have proven success in hematologic malignancies, their effectiveness in solid tumors has been largely unsuccessful thus far. We found that some olfactory receptors are expressed in a variety of solid tumors of different histologic subtypes, with a limited pattern of expression in normal tissues. Quantification of OR2H1 expression by qRT-PCR and Western blot analysis of 17 normal tissues, 82 ovarian cancers of various histologies, eight non-small cell lung cancers (NSCLCs), and 17 breast cancers demonstrated widespread OR2H1 expression in solid epithelial tumors with expression in normal human tissues limited to the testis. CAR T cells recognizing the extracellular domain of the olfactory receptor OR2H1 were generated with a targeting motif identified through the screening of a phage display library and demonstrated OR2H1-specific cytotoxic killing in vitro and in vivo, using tumor cells with spontaneous expression of variable OR2H1 levels. Importantly, recombinant OR2H1 IgG generated with the VH/VL sequences of the CAR construct specifically detected OR2H1 protein signal in 60 human lung cancers, 40 ovarian carcinomas, and 73 cholangiocarcinomas, at positivity rates comparable with mRNA expression and without OR2H1 staining in 58 normal tissues. CRISPR/Cas9-mediated ablation of OR2H1 confirmed targeting specificity of the CAR and the tumor-promoting role of OR2H1 in glucose metabolism. Therefore, T cells redirected against OR2H1-expressing tumor cells represent a promising therapy against a broad range of epithelial cancers, likely with an admissible toxicity profile.

TGF-ß-mediated silencing of genomic organizer SATB1 promotes Tfh cell differentiation and formation of intra-tumoral tertiary lymphoid structures.

The immune checkpoint receptor PD-1 on T follicular helper (Tfh) cells promotes Tfh:B cell interactions and appropriate positioning within tissues. Here, we examined the impact of regulation of PD-1 expression by the genomic organizer SATB1 on Tfh cell differentiation. Vaccination of CD4CreSatb1f/f mice enriched for antigen-specific Tfh cells, and TGF-ß-mediated repression of SATB1 enhanced Tfh differentiation of human T cells. Mechanistically, high Icos expression in Satb1-/- CD4+ T cells promoted Tfh cell differentiation by preventing T follicular regulatory cell skewing and resulted in increased isotype-switched B cell responses in vivo. Ovarian tumors in CD4CreSatb1f/f mice accumulated tumor antigen-specific, LIGHT+CXCL13+IL-21+ Tfh cells and tertiary lymphoid structures (TLS). TLS formation decreased tumor growth in a CD4+ T cell and CXCL13-dependent manner. The transfer of Tfh cells, but not naive CD4+ T cells, induced TLS at tumor beds and decreased tumor growth. Thus, TGF-ß-mediated silencing of Satb1 licenses Tfh cell differentiation, providing insight into the genesis of TLS within tumors.

Prevalence of Anemia and Compliance With NCCN Guidelines for Evaluation and Treatment of Anemia in Patients With Gynecologic Cancer.

BACKGROUND: NCCN recommends evaluation and treatment of all patients with cancer who have anemia. Few studies have evaluated the prevalence of anemia among patients with gynecologic cancer and compliance with the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Hematopoietic Growth Factors. METHODS: We performed a single-institution retrospective cohort study of patients diagnosed with primary gynecologic cancer between 2008 and 2018. We identified tumor registry-confirmed patients using ICD-O codes from the Synthetic Derivative database, a deidentified copy of Vanderbilt's electronic medical records. Patients were included if they were between ages 18 and 89 years, received initial care at Vanderbilt University Medical Center, and had a hemoglobin measurement within the first 6 months of diagnosis. Anemia was defined as a hemoglobin level ≤11 g/dL and was graded using CTCAE version 5.0. RESULTS: A total of 939 patients met inclusion criteria, with a median age of 60 years. The most common malignancy was uterine cancer. At the time of cancer diagnosis, 186 patients (20%) were noted to have anemia. Within 6 months of diagnosis, 625 patients (67%) had anemia, of whom 200 (32%) had grade 3 anemia and 209 (33%) underwent any evaluation of anemia, including 80 (38%) with iron studies performed. Of the patients with iron studies performed, 7 (9%) had absolute iron deficiency and 7 (9%) had possible functional iron deficiency. Among those with anemia within 6 months of diagnosis, 260 (42%) received treatment for anemia, including blood transfusion (n=205; 79%), oral iron (n=57; 22%), intravenous iron (n=8; 3%), vitamin B12 (n=37; 14%), and folate supplementation (n=7; 3%). Patients with ovarian cancer were significantly more likely to have anemia and undergo evaluation and treatment of anemia. CONCLUSIONS: Anemia is pervasive among patients with gynecologic cancer, but compliance with the NCCN Guidelines is low. Our data suggest that there are opportunities for improvement in the evaluation and management of anemia.

Numerical study of the vortex-induced electroosmotic mixing of non-Newtonian biofluids in a nonuniformly charged wavy microchannel: Effect of finite ion size.

We propose a micromixer for obtaining better efficiency of vortex induced electroosmotic mixing of non-Newtonian bio-fluids at a relatively higher flow rate, which finds relevance in many biomedical and biological applications. To represent the rheology of non-Newtonian fluid, we consider the Carreau model in this study, while the applied electric field drives the constituent components in the micromixer. We show that the spatial variation of the applied field, triggered by the topological change of the bounding surfaces, upon interacting with the non-uniform surface potential gives rise to efficient mixing as realized by the formation of vortices in the proposed micromixer. Also, we show that the phase-lag between surface potential leads to the formation of asymmetric vortices. This behavior offers better mixing performance following the appearance of undulation on the flow pattern. Finally, we establish that the assumption of a point charge in the paradigm of electroosmotic mixing, which is not realistic as well, under-predicts the mixing efficiency at higher amplitude of the non-uniform zeta potential. The inferences of the present analysis may guide as a design tool for micromixer where rheological properties of the fluid and flow actuation parameters can be simultaneously tuned to obtain phenomenal enhancement in mixing efficiency.

Efficacy of intensive orbitofrontal continuous Theta Burst Stimulation (iOFcTBS) in Obsessive Compulsive Disorder: A Randomized Placebo Controlled Study.

Transcranial magnetic stimulation (TMS) can non-invasively modulate specific brain regions in Obsessive-compulsive disorder (OCD). Citing orbito-frontal cortex (OFC) hyper-connectivity with striatum as the most consistent finding implicated in patho-physiologically of OCD, we aimed to study the effect of novel continuous Theta Burst Stimulation (cTBS) targeting OFC in OCD subjects on a randomized placebo control design. Thirty-three patients were randomly allocated to active cTBS (n= 18) and sham (n= 15) groups. They received 10 TBS sessions, 2 per day (total of 1200 pulses; intensive protocol) for 5 days in a week. The Yale Brown Obsessive Compulsive Scale (Y-BOCS), Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Rating Scale (HAM-A), and Clinical Global Impression-Severity (CGI-S) scores were assessed at baseline, after last session and at 2 weeks post-rTMS. On repeated measures-ANOVA, a significant group*time effect (from pretreatment to 2 weeks post TBS) for obsessions, compulsions, HAM-A, HAM-D, and CGI scores was found. But when controlled for confounding variables, only HAM-A scores and CGI effect retained statistical significance. We conclude that intensive OFC cTBS (iOFcTBS) in OCD is well tolerated with clinically significant improvements in anxiety symptoms and global severity. This improvement in anxiety symptoms could be due to modulations of state dependent dysregulation in OCD.

Leptin levels in alcohol dependent patients and their relationship with withdrawal and craving.

OBJECTIVE: Association between leptin plasma levels and alcohol craving has been seen previously. This study aims to research this correlation in a different population while comparing this correlation with respect to hyper-excitable state of alcohol withdrawal. METHODS: 25 patients of alcohol dependence were assessed for withdrawal symptoms and craving for alcohol. Leptin levels were measured on 1st day, @ the end of 1st week, @ the end of 3rd week of stopping alcohol. Withdrawal was assessed using CIWA-A at day 1 and day 7, craving was assessed using PENN's scale of craving at week 1 and week 3. Control group consisted of 15 first degree relatives. RESULTS: Leptin levels [t (38) = 2.95, p = 0.005] was significantly higher in alcohol dependent patients. Levels had no significant correlation with alcohol withdrawal scores [Leptin/BMI and CIWA Ar: r = 0.18, p = 0.40 on day 1] but had positive correlation with craving scores [Leptin/BMI and PACS: r = 0.684, p = 0.001]. CONCLUSION: This study shows that leptin, known for balancing the energy homeostasis of body, also seem to play a role in pathways of drug dependence and craving. This relation is independent of stress hormone axis.

Adverse events related to Trendelenburg position during laparoscopic surgery: recommendations and review of the literature.

PURPOSE OF REVIEW: Laparoscopy is routinely performed for the treatment and management of gynaecologic disorders. During gynaecologic laparoscopy, the patient is placed in the Trendelenburg position to optimize visualization and access to the pelvis. The Trendelenburg position may result in complications in many organ systems. RECENT FINDINGS: Trendelenburg positioning may cause rare, potentially life-threatening complications of the respiratory and cardiovascular systems. Case reports of visual field loss and cognitive aberrations following Trendelenburg positioning have been published. Few intervention studies have been performed evaluating attenuation of changes in intraocular pressure and haemodynamics. SUMMARY: This review summarizes possible complications related to the Trendelenburg position and current evidence regarding interventions to minimize the risk of complications.

Aggression as an independent entity even in psychosis - The role of cortisol.

Aggression is a common entity in psychiatric disorders, particularly psychotic disorders. Glucocorticoid hypofunction has been linked to abnormal forms of aggressive behavior in various studies in a 'possibly causal' role. We hypothesise that aggression, even among those having psychosis is associated with glucocorticoid alterations similar to those who are aggressive but not psychotic. To our knowledge, this is the first study attempting to look at the cortisol functioning in relation to both aggression and psychosis. The present study included 80 participants divided into four groups depending upon presence or absence of aggression and psychosis. Morning cortisol, afternoon cortisol and their variability were measured using ELISA. The groups were compared on measures of aggression, psychosis, morning cortisol, afternoon cortisol and their variability using standard statistical instruments. The present study found lower levels of morning cortisol, afternoon cortisol and cortisol variability among the aggressive group (vs. non aggressive group) and among the diseased group (vs. non diseased group). The differences were most marked for cortisol variability which was related to both aggression and psychosis independently. There were statistically significant correlation between cortisol variability and aggression, which was retained even after controlling for psychosis. There was no significant correlation of cortisol variability with psychosis severity (after controlling for aggression score) or with age, gender or duration of psychosis. We conclude that aggression, even among patients with psychosis, is an independent entity characterized by lower levels of morning cortisol and cortisol variability. The etio-pathology may lie in some altered neuro-immune parameters executed by cortisol and psychosis as trigger.

Aggression as an independent entity even in psychosis- the role of inflammatory cytokines.

BACKGROUND: Aggression is very common in psychosis (prevalence ranging from 34% to 70%) and is often the main or first symptom for which the patient receives medical attention. Studies have associated alteration in cytokine profiles among healthy persons with aggressive traits. We hypothesise that even among those with psychosis, aggression is an independent entity, irrespective of psychotic state and is associated with cytokine alterations. To our knowledge, this is the first study attempting to look at the inflammatory cytokines in aggressive psychotic patients. METHODS: Study included 80 participants divided into four groups viz. aggressive diseased, non aggressive diseased, aggressive non diseased and non aggressive non diseased depending upon presence or absence of aggression and psychosis. Interferon gamma(IFN-G), Interleukin 10(IL10) plasma concentrations and their ratio were measured using ELISA based assay kits read at absorbance of 450 nm wavelength using Double beam spectrophotometer. The four groups were compared on measures of aggression, psychosis, Interferon Gamma levels, Interleukin 10 levels, Proinflammatory: Antiinflammatory cytokine ratio using standard statistical instruments. RESULTS: In patients with psychosis, the cytokines IFN-G and IL10 were significantly lower compared to those without. The cytokines IFN-G and IL10 are both significantly associated both with aggression and psychosis. IL10, but not IFN-G is associated with aggression in absence of psychosis. The proinflammatory: antiinflammatory cytokine ratio, is more significantly associated with aggression, irrespective of psychosis. In fact, there is no significant relationship between the above ratio and psychosis. Strong correlation exists between the proinflammatory: antiinflammatory cytokine ratio and aggression scores, even after controlling for severity of psychosis. CONCLUSIONS: It may be concluded from this study that in spite of a high prevalence of aggression in patients of psychosis, it is more likely to be an independent entity associated with individual cytokine changes and increased proinflammatory: antiinflammatory cytokine ratio as its hallmark.