Scalp Cooling in Preventing Persistent Chemotherapy-Induced Alopecia: A Randomized Controlled Trial.

PURPOSE: Current studies of the efficacy of scalp cooling are limited by short-term duration. Therefore, we conducted a randomized controlled trial to evaluate the efficacy of scalp cooling in reducing persistent chemotherapy-induced alopecia (PCIA) 6 months after chemotherapy. METHODS: We conducted an open-label randomized controlled trial comparing scalp cooling versus control in newly diagnosed patients with breast cancer stages I-III scheduled to receive neoadjuvant or adjuvant chemotherapy with curative intent between December 2020 and August 2021. Patients were randomly assigned (2:1 ratio) to scalp cooling or usual clinical practice. The primary outcome was PCIA 6 months after chemotherapy. Hair thickness and density were measured using Folliscope 5.0. CIA-related distress was assessed using the CIA distress scale (CADS), with a higher score reflecting higher stress. RESULTS: The proportion of patients with PCIA at 6 months was 13.5% (12/89) in the scalp-cooling group and 52.0% (26/50) in the control group. The average difference in the change in hair thickness from baseline between the scalp-cooling and control groups was 9.0 µm in favor of the intervention group. The average difference in the change in hair density between intervention and control at the end of the study was -3.3 hairs/cm2. At 6 months after chemotherapy, the average difference in the change in CADS score between the intervention and control groups was -3.2 points, reflecting reduced CIA-related stress in the intervention group. CONCLUSION: Scalp cooling reduced the incidence of PCIA, primarily by increasing hair thickness compared with control. Scalp cooling is helpful in promoting qualitative hair regrowth. Yet, further research is necessary to observe longer-term benefits of scalp cooling.

Emulating trial to evaluate the effectiveness of routine supportive care on mortality among cancer patients experiencing distress at the time of diagnosis.

INTRODUCTION: Few studies have evaluated the effectiveness of interventions for distress during cancer diagnosis on clinical outcomes in a real-world setting. We aimed to evaluate whether routine information and psychosocial support to patients experiencing distress at the time of diagnosis could decrease the risk of mortality within 1 and 3 years after diagnosis. MATERIAL AND METHODS: We conducted a retrospective cohort study of 4880 newly diagnosed cancer patients who reported distress scores of ≥4 using the tablet or kiosk-based screening between July 2014 and December 2017 at a university-affiliated cancer center in Seoul, South Korea. We performed an emulated target trial with two groups: those that received information and psychosocial support and those that did not. Cox proportional hazards models were used to identify the associations between information and psychosocial support and all-cause mortality. RESULTS: Of all the patients, 16.6 % had routine information and psychosocial support. The hazard ratio (HR) for one-year mortality comparing participants with information and psychosocial support to those without it were 0.73 (95 % confidence interval (CI) = 0.54, 0.99). Age < 50 and 50 - <60 group had a stronger effect of information and psychosocial support on reducing mortality within one-year than these in age ≥ 60 (p for interaction = 0.03). In terms of three-year mortality, the HR comparing participants with information and psychosocial support to those without it was 0.93 (95 % CI = 0.76, 1.14). CONCLUSION: This large-scale real-world study suggests that timely psychosocial care benefits newly diagnosed cancer patients who had distress during pre-treatment period.

Cellular Efficacy of Fattigated Nanoparticles and Real-Time ROS Occurrence Using Microfluidic Hepatocarcinoma Chip System: Effect of Anticancer Drug Solubility and Shear Stress.

The objective of this study was to evaluate the effectiveness of organ-on-chip system investigating simultaneous cellular efficacy and real-time reactive oxygen species (ROS) occurrence of anticancer drug-loaded nanoparticles (NPs) using hepatocarcinoma cells (HepG2) chip system under static and hepatomimicking shear stress conditions (5 dyne/cm2). Then, the role of hepatomimetic shear stress exposed to HepG2 and drug solubility were compared. The highly soluble doxorubicin (DOX) and poorly soluble paclitaxel (PTX) were chosen. Fattigated NPs (AONs) were formed via self-assembly of amphiphilic albumin (HSA)-oleic acid conjugate (AOC). Then, drug-loaded AONs (DOX-AON or PTX-AON) were exposed to a serum-free HepG2 medium at 37 °C and 5% carbon dioxide for 24 h using a real-time ROS sensor chip-based microfluidic system. The cellular efficacy and simultaneous ROS occurrence of free drugs and drug-loaded AONs were compared. The cellular efficacy of drug-loaded AONs varied in a dose-dependent manner and were consistently correlated with real-time of ROS occurrence. Drug-loaded AONs increased the intracellular fluorescence intensity and decreased the cellular efficacy compared to free drugs under dynamic conditions. The half-maximal inhibitory concentration (IC50) values of free DOX (13.4 µg/mL) and PTX (54.44 µg/mL) under static conditions decreased to 11.79 and 38.43 µg/mL, respectively, under dynamic conditions. Furthermore, DOX- and PTX-AONs showed highly decreased IC50 values of 5.613 and 21.86 µg/mL, respectively, as compared to free drugs under dynamic conditions. It was evident that cellular efficacy and real-time ROS occurrence were well-correlated and highly dependent on the drug-loaded nanostructure, drug solubility and physiological shear stress.

Development of rapid and effective oil-spill response system integrated with oil collection, recovery and storage devices for small oil spills at initial stage: From lab-scale study to field-scale test.

In the present study, through the laboratory-to-field scale experiments and trials, we report the development and evaluation of an integrated oil-spill response system capable of oil collection, recovery (separation), and storage, for a timely and effective response to the initial stage of oil-spill accidents. With the laboratory-scale experiments, first, we evaluate that the water-surface waves tend to abate the oil recovery rate below 80% (it is above 95% for the optimized configuration without the waves), which is overcome by installing the hydrophilic (and oleophobic) porous structures at the inlet and/or near the water outlet of the separator. In the follow-up meso-scale towing tank tests with a scaled-up prototype, (i) we optimize the maneuverability of the assembled system depending on the speed and existence of waves, and (ii) evaluate the oil recovery performance (more than 80% recovery for the olive oil and Bunker A fuel oil). Although more thorough investigations and improvements are needed, a recovery rate of over 50% can be achieved for the newly enforced marine fuel oil (low sulfur fuel oil, LSFO) that was not targeted at the time of development. Finally, we perform a series of field tests with a full-scale system, to evaluate the rapid deployment and operational stability in the real marine environment. The overall floating balance and coordination of each functional part are sustained to be stable during the straight and rotary maneuvers up to the speed of 5 knots. Also, the collection of the floating debris (mimicking the spilled oil) is demonstrated in the field test. The present system is now being tested by the Korea Coast Guard and we believe that it will be very powerful to prevent the environmental damage due to the oil spills.

Structure-based drug discovery of a corticotropin-releasing hormone receptor 1 antagonist using an X-ray free-electron laser.

Thus far, attempts to develop drugs that target corticotropin-releasing hormone receptor 1 (CRF1R), a drug target in stress-related therapy, have been unsuccessful. Studies have focused on using high-resolution G protein-coupled receptor (GPCR) structures to develop drugs. X-ray free-electron lasers (XFELs), which prevent radiation damage and provide access to high-resolution compositions, have helped accelerate GPCR structural studies. We elucidated the crystal structure of CRF1R complexed with a BMK-I-152 antagonist at 2.75 Å using fixed-target serial femtosecond crystallography. The results revealed that two unique hydrogen bonds are present in the hydrogen bond network, the stalk region forms an alpha helix and the hydrophobic network contains an antagonist binding site. We then developed two antagonists-BMK-C203 and BMK-C205-and determined the CRF1R/BMK-C203 and CRF1R/BMK-C205 complex structures at 2.6 and 2.2 Å, respectively. BMK-C205 exerted significant antidepressant effects in mice and, thus, may be utilized to effectively identify structure-based drugs against CRF1R.

Efficacy of a novel remotely-generated ultrasonic root canal irrigation system for removing biofilm-mimicking hydrogel from a simulated isthmus model.

AIM: To evaluate the efficacy of a novel ultrasonic irrigation device, remotely-generated irrigation with a non-invasive sound field enhancement (RINSE) system, in removing biofilm-mimicking hydrogel from a simulated isthmus model and compare it with sonically- and ultrasonically-activated irrigation systems. METHODOLOGY: A polycarbonate root canal model containing two standardized root canals (apical diameter of 0.20 mm, 4% taper, 18 mm long with a coronal reservoir) connected by three isthmuses (0.40 mm deep, 2 mm high, 4 mm long) was used as the test model. The isthmuses were filled with a hydroxyapatite powder-containing hydrogel. The canals were filled with irrigant, and the models were randomly assigned to the following activation groups (n = 15): EndoActivator (EA), ultrasonically activated irrigation (UAI), and RINSE system (RS). Syringe irrigation (SI) with a 30G needle served as the control. Standardized images of the isthmuses were taken before and after irrigation, and the amount of hydrogel removed was determined using image analysis software and compared across groups using anova (p < .05). RESULTS: Hydrogel removal was significantly higher with the RS (83.7%) than with UAI, EA, or SI (p ≤ .01). UAI (69.2%) removed significantly more hydrogel than SI and EA (p < .05), while there was no significant difference between SI (24.3%) and EA (25.7%) (p = .978). CONCLUSIONS: RINSE system resulted in the most hydrogel removal, performing better than UAI or EA. The effect of RS was also not reliant on the insert or tip entering the pulp chamber or root canal, making it particularly useful in conservative endodontics.

A method for non-destructive microwave focusing for deep brain and tissue stimulation.

Non-invasive stimulation of biological tissue is highly desirable for several biomedical applications. Of specific interest are methods for tumor treatment, endometrial ablation, and neuro-modulation. In traditional neuro-modulation, single- and multi-coil transcranial stimulation techniques in low oscillation frequencies are utilized to non-invasively penetrate the skull and elicit action potentials in cortical neurons. Although these methods have been proven effective, tightly focusing these signals to localized regions is difficult. In recent years, microwave (MW) methods have seen an increase usage as a minimally invasive treatment modality for ablation and neuro-stimulation. Unlike low frequency signals, MW signals can be focused to localized sub-centimeter regions. In this work we demonstrate that a three-dimensional array of MW antennas can be used to tightly focus signals to a localized region in space within the human body with MW frequencies. Assuming an array of small MW loop antennas are placed around the body, the optimal amplitude and phase of each array element can be accurately determined to match an arbitrary desired field profile. The major innovation of the presented method is that the fields that penetrate the biological region are determined via computing numerical Green's functions (NGF) that are then used to drive an optimization algorithm. Using simplified models of regions in the human body, it is shown that the MW fields at 1 GHz can be focused to sub-centimeter sized "hot spots" at depths of several centimeters. The algorithm can be easily extended to more realistic models of the human body or for non-biological applications.

U-IMPACT: a universal 3D microfluidic cell culture platform.

The development of organs-on-a-chip has resulted in advances in the reconstruction of 3D cellular microenvironments. However, there remain limitations regarding applicability and manufacturability. Here, we present an injection-molded plastic array 3D universal culture platform (U-IMPACT) for various biological applications in a single platform, such as cocultures of various cell types, and spheroids (e.g., tumor spheroids, neurospheres) and tissues (e.g., microvessels). The U-IMPACT consists of three channels and a spheroid zone with a 96-well plate form factor. Specifically, organoids or spheroids (~500 µm) can be located in designated areas, while cell suspensions or cell-laden hydrogels can be selectively placed in three channels. For stable multichannel patterning, we developed a new patterning method based on capillary action, utilizing capillary channels and the native contact angle of the materials without any modification. We derived the optimal material hydrophilicity (contact angle of the body, 45-90°; substrate, <30°) for robust patterning through experiments and theoretical calculations. We demonstrated that the U-IMPACT can implement 3D tumor microenvironments for angiogenesis, vascularization, and tumor cell migration. Furthermore, we cultured neurospheres from induced neural stem cells. The U-IMPACT can serve as a multifunctional organ-on-a-chip platform for high-content and high-throughput screening.

Postherpetic Trigeminal Trophic Syndrome: A Case Report.

Trigeminal trophic syndrome (TTS) is a rare condition characterized by anesthesia, paresthesia, and facial ulceration involving the trigeminal dermatome secondary to self-manipulation of the skin after a peripheral or central injury to the trigeminal nerve or its branches. Differential diagnosis of TTS includes conditions presenting with chronic facial ulceration, such as various infectious diseases, malignancy, vasculitis, pyoderma gangrenosum and dermatitis artefacta. We report a case of postherpetic TTS and highlight the importance of early diagnosis and prompt treatment of this condition, which may commonly be misdiagnosed.

Divorce after breast cancer diagnosis and its impact on quality of life.

OBJECTIVE: This study aims to identify factors associated with divorce following breast cancer diagnosis and measures the impact of divorce on the quality of life (QoL) of patients. METHODS: We used cross-sectional survey data collected at breast cancer outpatient clinics in South Korea from November 2018 to April 2019. Adult breast cancer survivors who completed active treatment without any cancer recurrence at the time of the survey (N = 4,366) were included. The participants were classified into two groups: "maintaining marriage" and "being divorced," between at the survey and at the cancer diagnosis. We performed logistic regression and linear regression to identify the factors associated with divorce after cancer diagnosis and to compare the QoL of divorced and nondivorced survivors. RESULTS: Approximately 11.1/1,000 of married breast cancer survivors experienced divorce after cancer diagnosis. Younger age, lower education, and being employed at diagnosis were associated with divorce. Being divorced survivors had significantly lower QoL (Coefficient [Coef] = -7.50; 95% CI = -13.63, -1.36), social functioning (Coef = -9.47; 95% CI = -16.36, -2.57), and body image (Coef = -8.34; 95% CI = -6.29, -0.39) than survivors who remained married. They also experienced more symptoms including pain, insomnia, financial difficulties, and distress due to hair loss. CONCLUSION: Identifying risk factors of divorce will ultimately help ascertain the resources necessary for early intervention.

Comparing cleaning effects of gas and vapor bubbles in ultrasonic fields.

The dynamic actions of cavitation bubbles in ultrasonic fields can clean surfaces. Gas and vapor cavitation bubbles exhibit different dynamic behaviors in ultrasonic fields, yet little attention has been given to the distinctive cleaning effects of gas and vapor bubbles. We present an experimental investigation of surface cleaning by gas and vapor bubbles in an ultrasonic field. Using high-speed videography, we found that the primary motions of gas and vapor bubbles responsible for surface cleaning differ. Our cleaning tests under different contamination conditions in terms of contaminant adhesion strength and surface wettability reveal that vapor and gas bubbles are more effective at removing contaminants with strong and weak adhesion, respectively, and furthermore that hydrophobic substrates are better cleaned by vapor bubbles. Our study not only provides a better physical understanding of the ultrasonic cleaning process, but also proposes novel techniques to improve ultrasonic cleaning by selectively employing gas and vapor bubbles depending on the characteristics of the surface to be cleaned.

Coalescence of oil drops and films on micropillared substrates enabled by enhanced water drainage through pillar gaps.

Collecting or removing oil drops dispersed in water is essential in a range of industrial processes including oil recovery and oil spill cleanup. However, it is by no means easy to induce merging of oil drops with another body of oil due to slow drainage of the intervening water film. Here, we report immediate coalescence of oil drops with oil films that lie on micropillar arrays as immersed in various aqueous solutions. In addition to experimental demonstrations, we theoretically construct a regime map to predict whether the drop will bounce off or coalesce with the oil film, which is determined by the oil film thickness, geometry of the pillar array and liquid properties. Good agreement between theory and experiment indicates that micropillar arrays provide additional drainage paths of the intervening film, which helps drop-film coalescence. Our results suggest potential implications of utilizing oil-laden microporous structures to achieve efficient demulsification of oil drops in contaminated water.

Crosstalk between WNT and STAT3 is mediated by galectin-3 in tumor progression.

BACKGROUND: Aberrant activation of the WNT/ß-catenin and STAT3 signaling pathways plays a critical role in cancer progression. However, direct targeting of these pathways as an anti-cancer therapeutic approach needs to be reconsidered due to its serious side effects. Here, we demonstrate that overexpression of WNT induces STAT3 activation in a galectin-3-dependent manner. METHODS: We investigated how galectin-3 mediates the crosstalk between WNT/ß-catenin and STAT3 signaling and whether inhibition of galectin-3 can reduce gastric cancer. The molecular mechanisms were analyzed by biochemical assays using cultured gastric cancer cells, patient tissues, and genetically engineered mice. Moreover, we confirm of therapeutic effects of GB1107, a cell-penetrating galectin-3 specific inhibitor, using orthotopic gastric cancer-bearing mice RESULTS: Increased levels of galectin-3 and STAT3 phosphorylation were detected in the stomach tissues of WNT1-overexpressing mouse models. Also, high expression levels and co-localization of ß-catenin, pSTAT3, and galectin-3 in patients with advanced gastric cancer were correlated with a poorer prognosis. Galectin-3 depletion significantly decreased STAT3 Tyr705 phosphorylation, which regulates its nuclear localization and transcriptional activation. A peptide of galectin-3 (Y45-Q48) directly bound to the STAT3 SH2 domain and enhanced its phosphorylation. GB1107, a specific membrane-penetrating inhibitor of galectin-3, significantly reduced the activation of both STAT3 and ß-catenin and inhibited tumor growth in orthotopic gastric cancer-bearing mice. CONCLUSIONS: We propose that galectin-3 mediates the crosstalk between the WNT and STAT3 signaling pathways. Therefore GB1107, a galectin-3-specific inhibitor, maybe a potent agent with anti-gastric cancer activity. Further studies are needed for its clinical application in gastric cancer therapy.

Direct recovery of spilled oil using hierarchically porous oil scoop with capillary-induced anti-oil-fouling.

The pitcher plant has evolved its hierarchically grooved peristome to enhance a water-based slippery system for capturing insects with oil-covered footpads. Based on this, we proposed a hierarchically porous oil scoop (HPOS) with capillary-induced oil peel-off ability for repeatable spilled oil recovery. As the HPOS scoops oil-water mixture, water passes through the hole while the oil is confined within a curved geometry. The filter in HPOS has three levels of porous structures; (1) 3D-printed mesh structure with sub-millimeter scale hole to filter out oil from an oil-water mixture, (2) internal micropore in fibers enhancing capillarity and water transport, (3) O2 plasma-induced high-aspect-ratio nanopillar structures imposing anti-oil-fouling property with capillary-induced oil peeling. As the oil-contaminated HPOS makes contact with water, water meniscus rises and peels off the oil immediately at the air-water interface. The oil-peel-off ability of the HPOS would prevent pores from clogging by oils for reuse. The study demonstrated that the HPOS recovers highly viscous oil (up to 5000 mm2·s-1) with a high recovery rate (>95%), leaving the filtered water with low oil content (<10 ppm), which satisfies the discharge criterion of 15 ppm.

Effect of Surface Roughness on Crystal Size of Manganese Phosphate Coating of Carbon Steel.

In this study, the correlation between surface roughness of carbon steel and crystal size of manganese phosphate coatings has been investigated. The microstructure and surface morphology of the coatings were analyzed by SEM, XRD. The surface roughness test was carried out in order to calculate Ra value by atomic force microscopy (AFM). Also, the tribology property of manganese phosphate coating was tested by ball-on disk. XRD showed that (Mn,Fe)5H2(PO4)4·4H2O in manganese phosphate coating layer was formed by the chemical reaction between manganese phosphate and elements in carbon steel. Also, (Mn,Fe)5H2(PO4)4 · 4H2O was observed to be formed in all manganese phosphate conversion coating. With regard to the effects of surface roughness on manganese phosphate coatings, it can be seen that there is an increase of the crystal size on manganese phosphate coating as the surface roughness of carbon steel decreased. The increase of crystal size by the surface roughness had effect on the tribology property and electrochemical property. It was approved that friction coefficient of manganese phosphate coating is remarkably improved as the surface roughness of carbon steel become rough.

Effect of Surface Activation Agents on Manganese Phosphate Coating of Carbon Steel.

The surface activation agents have been used to form a high quality coating layer on manganese phosphate process. The role of surface activation agents increases the nucleation sites, which leads to obtain a finer phosphate coating. In this study, the effects of surface activation agents on manganese phosphate coating were investigated by changing the chemical composition ratio between sodium pyrophosphate and manganese carbonate. The morphology, chemical composition and corrosion resistance of the coatings were analyzed by SEM, XRD, EDS, XPS and electrochemical polarization method, respectively. Also, the tribology property of manganese phosphate coating was tested by ball-on disk. In the results of EDS analysis, coating layer consists of elements such as Mn, P, Fe, O, and C. XRD showed that (Mn,Fe)5H2(PO4)4 · 4H2O in manganese phosphate coating layer was formed by the chemical reaction between manganese phosphate and elements in carbon steel. With regard to the effects of surface activation agents on the manganese phosphate coatings, it can be seen that there is an increase of the crystal size on phosphate coating as the content of sodium pyrophosphate increased. The increase of sodium pyrophosphate had effect on the tribology property under the condition of spindle oil retention. Corrosion resistance was improved for manganese carbonate (3 g/L) and sodium pyrophosphate (3 g/L) coating with the ratio of 1:1. Also, better tribology property was observed for manganese carbonate (3 g/L) and sodium pyrophosphate (15 g/L) with the ratio of 1:5.

A case of multinucleate cell angiohistiocytoma in a 14-year-old boy showing two different clinical and histopathological findings.

Multinucleate cell angiohistiocytoma (MCAH) is a rare cutaneous disease entity characterized by multiple red-to-brown or violaceous papules usually located on the acral regions, such as the face and the distal arms and legs. It affects elderly women more than men and rarely occurs at a young age. The exact pathogenic mechanism of MCAH is not yet clearly understood. We report an exceptionally rare case of a 14-year-old boy who presented with multiple asymptomatic erythematous papules and a single flat brownish plaque on the left chest. The brownish plaque lesion histologically showed proliferation of dilated small vessels in the upper-mid dermis and numerous oddly shaped multinucleate cells intermingled with lymphocytes and macrophages. The erythematous papules also showed dilated small vessels in the upper-mid dermis and multiple interstitial histiocytic infiltrations, but no multinucleate cells were detected. In immunohistochemistry studies, CD68 and vimentin staining were positive for both specimens. Based on the clinicopathological findings and immunohistochemistry studies, MCAH was diagnosed. To the best of our knowledge, this is the first case report of MCAH occurring in young age and showing two different clinical and histological phases at the same time.

Crystal Structure of Human Dual-Specificity Tyrosine-Regulated Kinase 3 Reveals New Structural Features and Insights into its Auto-phosphorylation.

Dual-specificity tyrosine-regulated kinases (DYRKs) auto-phosphorylate a critical tyrosine residue in their activation loop and phosphorylate their substrate on serine and threonine residues. The auto-phosphorylation occurs intramolecularly and is a one-off event. DYRK3 is selectively expressed at a high level in hematopoietic cells and attenuates erythroblast development, leading to anemia. In the present study, we determined the crystal structure of the mature form of human DYRK3 in complex with harmine, an ATP competitive inhibitor. The crystal structure revealed a phosphorylation site, residue S350, whose phosphorylation increases the stability of DYRK3 and enhances its kinase activity. In addition, our structural and biochemical assays suggest that the N-terminal auto-phosphorylation accessory domain stabilizes the DYRK3 protein, followed by auto-phosphorylation of the tyrosine of the activation loop, which is important for kinase activity. Finally, our docking analysis provides information for the design of novel and potent therapeutics to treat anemia.

Constitutive activation of T cells by γ2-herpesviral GPCR through the interaction with cellular CXCR4.

Members of the herpesviral family use multiple strategies to hijack infected host cells and exploit cellular signaling for their pathogenesis and latent infection. Among the most intriguing weapons in the arsenal of pathogenic herpesviruses are the constitutively active virally-encoded G protein-coupled receptors (vGPCRs). Even though vGPCRs contribute to viral pathogenesis such as immune evasion and proliferative disorders, the molecular details of how vGPCRs continuously activate cellular signaling are largely unknown. Here, we report that the vGPCR of Herpesvirus saimiri (HVS), an oncogenic γ2-herpesvirus, constitutively activates T cells via a heteromeric interaction with cellular CXCR4. Constitutive T cell activation also occurs with expression of the vGPCR of Kaposi's sarcoma-associated herpesvirus (KSHV), but not the vGPCR of Epstein-Barr virus. Expression of HVS vGPCR down-regulated the surface expression of CXCR4 but did not induce the degradation of the chemokine receptor, suggesting that vGPCR/CXCR4 signaling continues in cytosolic compartments. The physical association of vGPCR with CXCR4 was demonstrated by proximity ligation assay as well as immunoprecipitation. Interestingly, the constitutive activation of T cells by HVS vGPCR is independent of proximal T cell receptor (TCR) signaling molecules, such as TCRß, Lck, and ZAP70, whereas CXCR4 silencing by shRNA abolished T cell activation by vGPCRs of HVS and KSHV. Furthermore, previously identified inactive vGPCR mutants failed to interact with CXCR4. These findings on the positive cooperativity of vGPCR with cellular CXCR4 in T cell activation extend our current understanding of the molecular mechanisms of vGPCR function and highlight the importance of heteromerization for GPCR activity.