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INTRODUCTION Postoperative pain management is an essential aspect of perioperative care for patients undergoing emergency Cesarean sections. Adequate pain control not only improves patient comfort and satisfaction but also facilitates early mobilization, reduces the risk of complications, and shortens hospital stays. Transverse abdominis plane (TAP) block is a well-established technique for providing analgesia to the anterior abdominal wall, which can significantly reduce postoperative pain. In recent years, ultrasound guidance has been increasingly used to improve the accuracy and safety of TAP block. This research article aims to review the use of ultrasound-guided TAP block for postoperative analgesia in patients undergoing emergency Cesarean Sections. Methodology : A total of 60 patients who underwent Emergency Cesarean Sections were included in the study. All received bilateral US-guided TAP blocks with either ropivacaine 0.5% 20 ml on each side i. e. 40 ml total or saline. All participants received a spinal anaesthetic with bupivacaine, followed by postoperative acetaminophen, non-steroidal anti-inflammatory drugs, and patient-controlled i.v. tramadol . Each patient was assessed 24 h after delivery for PCA Tramadol usage, average pain score, nausea, vomiting, itch and duration of hospital stay. Results and Conclusion Out of the total 60 patients , 30 were in the study group and 30 in placebo group. Total PCA Tramadol use in 24 h was reduced in the study group compared with the placebo group ( P

Abstract Background Double chambered right ventricle is a rare congenital heart disease that is characterised by the presence of an anomalous muscle bundle that divides the right ventricle into a low pressure superior (distal) chamber and a high pressure inferior (proximal) chamber. It is found in association with a ventricular septal defect in 90% cases with other associations being tetralogy of Fallot, transposition of great vessels, atrial septal defect and Ebstein’s anomaly. On the other hand, subaortic membrane is a form of discrete subaortic stenosis that is characterised by a membranous diaphragm in the subvalvular location of the left ventricular outflow tract. Both of these entities are responsible for causing subvalvular outflow tract obstruction. The occurrence of double chambered right ventricle in association with subaortic membrane is an extremely rare entity with only a few case reports available in the literature. Case report A 13-year-old male child with history of chest pain and palpitations presented to the outpatient department of a tertiary care center. Transthoracic echocardiography revealed a subaortic membrane producing a pressure gradient across the left ventricular outflow tract with dilatation of the right atrium and right ventricle which could not be fully evaluated on echocardiography. Cardiac computed tomography was then performed which additionally revealed an anomalous muscle bundle coursing across the right ventricle from the septum to the subinfundibular region creating a double chambered right ventricle. The patient was then taken up for reconstruction of right ventricular outflow tract and resection of subaortic membrane. Conclusion Right and left outflow tract obstructions are rare congenital lesions which when seen in combination, become even more infrequent. Echocardiography is a robust tool that detects turbulent flow to identify such lesions. However, poor acoustic window may sometimes result in missing these lesions and computed tomography in such situations can play an important role in detection as well as complete preoperative imaging evaluation.

Abstract Background Phyllodes tumours (PT) of the breast are rare primary breast neoplasms, mostly seen in fourth to fifth decades of life. These tumours are exceptionally rare in children and young females. The clinico-radiological features often overlap with fibroadenoma. Though imaging plays a pivotal role in providing an initial diagnostic approach, the final confirmation is dispensed on histopathology, which further classifies PT into either benign, low-grade malignant (borderline), or high-grade malignant. On reviewing the literature, only 20 cases have been reported so far in young females, with majority of them being benign and very few numbers of malignant PT. Case presentation Herein, we report the clinical and imaging features of PT in four young females, of benign, borderline and high-grade malignant categories as confirmed on histopathology, thereby adding few more numbers to the already existing cases. Additionally, our fourth case depicts rare presentation of high-grade malignant recurrent PT in adolescent female with nodal and unilateral ovarian metastases. Conclusions In conclusion, a possibility of PT should be considered in differential diagnosis in a large rapidly enlarging breast mass even in young females with characteristic imaging features, as it alters the plan of management.

Abstract Background Hydatid disease is a parasitic infection which is endemic in multiple regions across the globe including Indian subcontinent. Although it commonly affects the liver and other solid organs, isolated involvement of the heart is relatively uncommon. Cardiac hydatidosis can be confidently diagnosed on echocardiography, but cross-sectional imaging by computed tomography (CT) or magnetic resonance imaging (MRI) provides accurate information about its location, extent, and multiplicity. Multiple case studies of cardiac hydatid disease have been reported in the literature. However, cardiac hydatidosis with extension into pulmonary vasculature has not been reported commonly. This case report highlights this rare association, with stress upon the altered surgical management. Case presentation A 50-year-old patient presented with atypical chest pain to the cardiology department of a tertiary care hospital where he underwent multiple blood tests as well as electrocardiography (ECG) and echocardiography as part of the routine examination. Echocardiography revealed a large, multicystic mass invading the posterolateral wall of left ventricle (LV) with no internal vascularity and was provisionally diagnosed as hydatid disease. Subsequent CT study confirmed a large multicystic lesion with the presence of another smaller lesion invading the left atrial appendage (LAA). In order to evaluate the vascular and mediastinal invasion, cardiac MRI was then performed which revealed invasion of right pulmonary artery (PA), right superior pulmonary vein (PV) as well as compression of superior vena cava (SVC) by the smaller lesion. A final diagnosis of cardiac hydatidosis with invasion into right PA and right superior PV was made. Treatment plan for the patient changed, who then underwent an additional reconstruction of right PA and right superior PV after cyst removal. Conclusions Cardiac hydatid disease is a rare but potentially lethal condition, which tends to show slow growth and local invasion. The diversity of findings in such rare cases makes individual surgical approach extremely valuable with preoperative radiological imaging becoming indispensable for correct localization and appropriate planning. Our case report highlights rare association of cardiac hydatidosis with invasion of both pulmonary artery and vein, which eventually altered the surgical management of patient.

Abstract Background Cystic lymphangiomas are benign vascular malformations of lymphatic differentiation. They usually occur in childhood and are commonly seen in the head and neck region. Lymphangioma of the gallbladder is extremely rare, and only a handful of cases have been reported in the literature. Case presentation A 56-year-old female presented to the outpatient department for evaluation of right upper quadrant abdominal pain which had been bothering her for the past few months. Abdominal ultrasonography revealed an ill-defined septated cystic lesion surrounding the gallbladder (GB) which was initially thought to be a collection. However, contrast-enhanced computed tomography of abdomen showed a well-marginated fluid density lesion in the gall bladder fossa which was insinuating around the gall bladder and was encasing it. No intralesional enhancement was seen after contrast administration. MRI confirmed the well-defined, multiseptated lesion without any solid component in the gall bladder fossa encasing the GB but without any abnormal communication with the biliary tree. Therefore, a final diagnosis of slow flow lymphatic malformation was formulated. The patient underwent exploratory laparotomy, and the mass was resected en bloc with the GB. Histological evaluation was consistent with lymphatic malformation. Conclusions GB lymphangioma is a rare entity and is difficult to diagnose. While the imaging characteristics are essentially similar to lymphangiomas elsewhere in the body, the location is peculiar and should warrant a thorough evaluation by the means of CT and more importantly MRI.

Background:. Differences of sex development (DSD or disorders of sex development) are uncommon congenital conditions, characterized by atypical development of chromosomal, gonadal, or anatomic sex. Objective:. Dermatologic care is an important component of the multidisciplinary care needed for individuals with DSD. This article discusses the most common primary dermatologic manifestations of DSD in addition to the cutaneous manifestations of hormonal and surgical therapies in individuals with DSD. Data sources:. Published articles including case series and case reports on PubMed. Study selections:. Selection was conducted by examining existing literature with a team of multidisciplinary specialists. Methods:. Narrative review. Limitations:. This article was not conducted as a systematic review. Results:. In Klinefelter syndrome, refractory leg ulcers and incontinentia pigmenti have been described. Turner syndrome is associated with lymphatic malformations, halo nevi, dermatitis, and psoriasis. Virilization can be seen in some forms of congenital adrenal hyperplasia, where acne and hirsutism are common. Conclusion:. Dermatologists should consider teratogenic risk for treatments of skin conditions in DSD depending on pregnancy potential. Testosterone replacement, commonly used for Klinefelter syndrome, androgen insensitivity syndrome, 5-alpha reductase deficiency, gonadal dysgenesis, or ovotesticular DSD, may cause acne.

Introduction Pyomyositis denotes primary pyogenic infection of skeletal muscle. It is predominantly a disease of tropical countries. It usually involves the largest muscle groups around the pelvic girdle and lower extremities. Primary reasons for delay in diagnosis are its low incidence and vague presentation [7]. This delay can result in complications such as extension into and destruction of an adjacent joint, sepsis and, even death. Our study is aimed to highlight the extent and sequence of treatment protocol required for good management of these patients. Methods We retrospectively analyzed our experience with a series of 14 pediatric patients with primary pyomyositis who were treated and followed up. There were five girls and nine boys. All 14 patients underwent plain radiographs, USG and MRI of the affected area followed by surgical drainage and a course of antibiotics. Patients were followed up with weekly CRP. Results Six out of 14 (42.9 %) patients had a history of mild trauma. Ileopsoas muscle was involved in 4 patients, 3 cases in which the gluteals or quadriceps were involved, 2 cases with obturator muscle involvement and 2 cases in which adductors were the infection site. All 14 patients were treated surgically. Conclusion Our study shows that early diagnosis, complete drainage of the purulent material and the use of appropriate antibiotic therapy are the key determinants of successful treatment that lead to complete resolution in the majority of cases.

Introduction Distal humerus fractures are relatively rare and being intra-articular are difficult to manage. As the number of elderly people grows steadily and also with increasing use of motor vehicles in the developing countries, it can be said that the frequency of intraarticular fractures of the distal humerus will increase similar to the fractures of the distal end of the radius, hip, and spine. There are several treatment plans for managing intraarticular fractures of the distal humerus depending on fracture anatomy. We conducted this study to assess which approach is superior, closed percutaneous reduction with K-wires or ORIF. Methods A total of 30 patients who satisfied the inclusion criteria were included, out of which 16 patients underwent ORIF and 14 patients underwent closed reduction and percutaneous pinning (СRPP). Patients included were between 21–50 years of age with intraarticular nonpathological closed distal humerus fractures without preoperative neurovascular deficit and presented less than 10 days between the fracture event and treatment. Results In our study, mean age of patients undergoing CRPP was 28.1 years while the mean age of patients undergoing ORIF was 30.1 years. This study showed that distal humerus fractures are more common in younger age groups. In our study, mean arc of motion at 6 months postoperatively in patients which underwent CRPP was 106.07 degrees while the mean arc of motion in patients which underwent ORIF was 80.94 degrees. In patients who underwent ORIF, only 6.2 % (1/16) had excellent outcome, 56.3 % (9/16) patients had good outcomes, 31.3 % (5/16) patients had fair outcomes, and 6.2 % (1/16) had poor outcome. It was found that out of a total of 14 patients which underwent CRPP, only 7.1 % (1/14) had cutaneous impingement. Fracture union occurred in 100 % of patients except 3 patients in ORIF group; however, they had partial union up till 6 months of follow-up. Conclusion Our study concludes that even displaced intra-articular fractures of the distal humerus can be satisfactorily treated with closed reductions and percutaneous pinning.

Insulinomas are a rare cause of persistent hypoglycemia in a previously healthy child. In addition to symptoms of hypoglycemia, individuals with insulinomas usually present with a history of incessant caloric intake and weight gain due to a constant need to counter hypoglycemia. In addition to an extensive review of the literature, we report the first case of an insulinoma coexisting with reduced appetite secondary to anorexia nervosa in an adolescent female.

Abstract Background Cancer cells develop resistance to chemotherapeutic intervention by excessive formation of stress granules (SGs), which are modulated by an oncogenic protein G3BP2. Selective control of G3BP2/SG signaling is a potential means to treat non-small cell lung cancer (NSCLC). Methods Co-immunoprecipitation was conducted to identify the interaction of MG53 and G3BP2. Immunohistochemistry and live cell imaging were performed to visualize the subcellular expression or co-localization. We used shRNA to knock-down the expression MG53 or G3BP2 to test the cell migration and colony formation. The expression level of MG53 and G3BP2 in human NSCLC tissues was tested by western blot analysis. The ATO-induced oxidative stress model was used to examine the effect of rhMG53 on SG formation. Moue NSCLC allograft experiments were performed on wild type and transgenic mice with either knockout of MG53, or overexpression of MG53. Human NSCLC xenograft model in mice was used to evaluate the effect of MG53 overexpression on tumorigenesis. Results We show that MG53, a member of the TRIM protein family (TRIM72), modulates G3BP2 activity to control lung cancer progression. Loss of MG53 results in the progressive development of lung cancer in mg53 -/- mice. Transgenic mice with sustained elevation of MG53 in the bloodstream demonstrate reduced tumor growth following allograft transplantation of mouse NSCLC cells. Biochemical assay reveals physical interaction between G3BP2 and MG53 through the TRIM domain of MG53. Knockdown of MG53 enhances proliferation and migration of NSCLC cells, whereas reduced tumorigenicity is seen in NSCLC cells with knockdown of G3BP2 expression. The recombinant human MG53 (rhMG53) protein can enter the NSCLC cells to induce nuclear translation of G3BP2 and block arsenic trioxide-induced SG formation. The anti-proliferative effect of rhMG53 on NSCLC cells was abolished with knockout of G3BP2. rhMG53 can enhance sensitivity of NSCLC cells to undergo cell death upon treatment with cisplatin. Tailored induction of MG53 expression in NSCLC cells suppresses lung cancer growth via reduced SG formation in a xenograft model. Conclusion Overall, these findings support the notion that MG53 functions as a tumor suppressor by targeting G3BP2/SG activity in NSCLCs.

Abstract Monitoring pathological mechano-acoustic signals emanating from the lungs is critical for timely and cost-effective healthcare delivery. Adventitious lung sounds including crackles, wheezes, rhonchi, bronchial breath sounds, stridor or pleural rub and abnormal breathing patterns function as essential clinical biomarkers for the early identification, accurate diagnosis and monitoring of pulmonary disorders. Here, we present a wearable sensor module comprising of a hermetically encapsulated, high precision accelerometer contact microphone (ACM) which enables both episodic and longitudinal assessment of lung sounds, breathing patterns and respiratory rates using a single integrated sensor. This enhanced ACM sensor leverages a nano-gap transduction mechanism to achieve high sensitivity to weak high frequency vibrations occurring on the surface of the skin due to underlying lung pathologies. The performance of the ACM sensor was compared to recordings from a state-of-art digital stethoscope, and the efficacy of the developed system is demonstrated by conducting an exploratory research study aimed at recording pathological mechano-acoustic signals from hospitalized patients with a chronic obstructive pulmonary disease (COPD) exacerbation, pneumonia, and acute decompensated heart failure. This unobtrusive wearable system can enable both episodic and longitudinal evaluation of lung sounds that allow for the early detection and/or ongoing monitoring of pulmonary disease.

The idea of a 'private practising anaesthesiologist'is generally that of a busy practitioner running from case to case, from one nursing home to the other, at all times of the day and night with no time for academics, teaching and family life.But is that really so? Is taking up a career in private practice going to be so full of hardships?There are several advantages of choosing private practice in anaesthesia. To survive in private practice, you need to be very confident in your work, skilful, punctual and good in communication. You can be your own master as a private practitioner. Private practice in anaesthesia is both challenging and interesting. This article, written by private practitioners in anaesthesia who have gone through the exciting and mundane phases of private practice examines the pro and cons of private practice; this can possibly help postgraduate students contemplating to take up private practice as a career.

Extensive work is being done to form targeted drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; however, it is imperative to have a safe and effective vaccine against the same to win the war against this pandemic. For creating an efficacious vaccine, a proper animal model needs to be selected which can have an acceptable similarity of response as well as effects when administered to humans. For the present research, extensive search was conducted in MEDLINE and bioRxiv and medRxiv servers which were published in the English language from January 1, 2020, to August 20, 2020. Search terms included animal models, SARS-CoV-2, COVID-19, immune response against coronavirus, nonhuman primates, mice, ferrets, and macaques. In our study, creating an adequate immune response mimicking the response as in humans, as the endpoint, was considered as inclusion criterion while assessment of any additional therapies like safety as well as minimal tolerable dose using animal models as well as formation of adequate sample size of these models against COVID-19 was not considered. In our search, 163 articles were shortlisted, of them only 20 articles were finally included in our study which addressed to our inclusion and exclusion criterion. Our research articles focused on nonhuman primates, mice, hamsters, ferrets, cats, and dogs, with the main goal to investigate the role of animal models in the pathogenesis of COVID-19. It was evident in our research that animal models only mimic limited signs and symptoms experienced in COVID infection as compared to infections in humans. However, they are still essential to understand the pathogenesis, transmissibility of viral particles, and vaccine testing.

Background: Osteoarthritis and osteoporosis are the most prevalent musculoskeletal disorders (MSDs) in middle aged and elderly individuals and affect their quality of life (QOL). The presence of both these disorders is rarely reported in an individual patient. This study was conducted with the aim to assess this association using Dual-energy X-ray absorptiometry (DEXA) as a measure of bone mineral density (BMD) in patients undergoing hip and knee arthroplasty. Methods: Between August 2015 and August 2018, 71 patients were selected as the study participants. The inclusion criteria included age of higher than 50 years and presence of ‎primary or secondary arthritic conditions. The exclusion criteria were age of below 50 years, prolonged steroid intake (3 months), metabolic disease, and performance of ‎arthroplasty for the management of fractures. Results: The incidence rate of osteoporosis was found to be higher in higher age groups of patients undergoing arthroplasty. Furthermore, there was no statistical difference in the T-scores with respect to the sex of the patients. Conclusion: Osteoarthritis and osteoporosis can occur simultaneously in an individual. The development of osteoarthritis does not prevent the development of generalized osteoporosis in an individual patient.

Chronic myeloid leukemia (CML) is caused by the Philadelphia (Ph+) chromosome carrying the BCR-ABL oncogene, a constitutively active tyrosine kinase. The discovery of imatinib represents a major success story in the treatment against CML. However, mutations in the BCR-ABL kinase domain are a major cause of resistance to imatinib, demonstrating that BCR-ABL remains a critical drug target. Here, we investigate a novel small molecule inhibitor, OGP46, for its inhibitory activity against K562, a panel of murine BaF3 cell lines stably expressing either wild-type BCR-ABL or its mutant forms, including T315I. OGP46 exhibits potent activity against imatinib-resistant BCR-ABL mutations, including T315I. OGP46 induced cell differentiation accompanied by G0/G1 cell-cycle arrest and suppressed the colony formation capacity of cells. Treatment with OGP46 significantly decreased the mRNA and protein expression of BCR-ABL in K562 and BaF3-p210-T315I cells. Mechanistically, the anti-cancer activity of OGP46 induced by cell differentiation is likely through the BCR-ABL/JAK-STAT pathway in native BCR-ABL and mutant BCR-ABL, including T315I, of CML cells. Our findings highlight that OGP46 is active against not only native BCR-ABL but also 11 clinically relevant BCR-ABL mutations, including T315I mutation, which are resistant to imatinib. Thus, OGP46 may be a novel strategy for overcoming imatinib-resistance BCR-ABL mutations, including T315I.

Abstract Mechano-acoustic signals emanating from the heart and lungs contain valuable information about the cardiopulmonary system. Unobtrusive wearable sensors capable of monitoring these signals longitudinally can detect early pathological signatures and titrate care accordingly. Here, we present a wearable, hermetically-sealed high-precision vibration sensor that combines the characteristics of an accelerometer and a contact microphone to acquire wideband mechano-acoustic physiological signals, and enable simultaneous monitoring of multiple health factors associated with the cardiopulmonary system including heart and respiratory rate, heart sounds, lung sounds, and body motion and position of an individual. The encapsulated accelerometer contact microphone (ACM) utilizes nano-gap transducers to achieve extraordinary sensitivity in a wide bandwidth (DC-12 kHz) with high dynamic range. The sensors were used to obtain health factors of six control subjects with varying body mass index, and their feasibility in detection of weak mechano-acoustic signals such as pathological heart sounds and shallow breathing patterns is evaluated on patients with preexisting conditions.

Previously, we reported that Y6, a new epigallocatechin gallate derivative, is efficacious in reversing doxorubicin (DOX)--mediated resistance in hepatocellular carcinoma BEL-7404/DOX cells. In this study, we evaluated the efficacy of Y6 in reversing drug resistance both in vitro and in vivo by determining its effect on the adenosine triphosphate-binding cassette protein B1 transporter (ABCB1 or P-glycoprotein, P-gp). Our results showed that Y6 significantly sensitized cells overexpressing the ABCB1 transporter to anticancer drugs that are ABCB1 substrates. Y6 significantly stimulated the adenosine triphosphatase activity of ABCB1. Furthermore, Y6 exhibited a higher docking score as compared with epigallocatechin gallate inside the transmembrane domain of ABCB1. In addition, in the nude mouse tumor xenograft model, Y6 (110 mg/kg, intragastric administration), in combination with doxorubicin (2 mg/kg, intraperitoneal injection), significantly inhibited the growth of BEL-7404/DOX cell xenograft tumors, compared to equivalent epigallocatechin gallate. In conclusion, Y6 significantly reversed ABCB1-mediated multidrug resistance and its mechanisms of action may result from its competitive inhibition of the ABCB1 drug efflux function. KEY WORDS: Epigallocatechin gallate (EGCG), 5,3′,4′,3″,4″,5″-6-O-ethyl-EGCG (Y6), Drug resistance, Resistance reversal, ABCB1, P-gp

Single point incremental forming has shown immense potential in the manufacture of prototypes. The sheet metal deformation in this technique is carried out by a small hemispherical or flat tool that moves from the sheet periphery to the sheet center while also pushing the sheet down. Simulations of single point incremental forming can be a tedious task since the area required to be formed is large and the two sheet contact area is fairly small. The effect of tool however, affects the entire geometry by causing deflections and radial strains. Hence, it becomes essential to understand the effect of certain parameters that influence the simulation results for this forming process. The paper aims to study factors influencing the simulation of single point incremental forming process. It gives a description of techniques employed to simulate non-linear behavior of sheet metal forming along with the implicit and explicit methodology. Information on the selection of element type including Reduced Enhanced Solid-Shell element is presented. Techniques employed to avoid locking are also discussed.

Cabozantinib (CBZ) is a small molecule tyrosine kinase receptor inhibitor, which could also inhibit the ABCG2 transporter function. Therefore, CBZ could re-sensitize cancer cells that are resistant to ABCG2 substrate drugs including topotecan (TPT). However, its reversal effect against TPT resistance has not been tested in a TPT-induced resistant cancer model. In this study, a new TPT selected human non-small cell lung cancer (NSCLC)-resistant cell model NCI-H460/TPT10 with ABCG2 overexpression and its parental NCI-H460 cells were utilized to investigate the role of CBZ in drug resistance. The in vitro study showed that CBZ, at a non-toxic concentration, could re-sensitize NCI-H460/TPT10 cells to TPT by restoring intracellular TPT accumulation via inhibiting ABCG2 function. In addition, the increased cytotoxicity by co-administration of CBZ and TPT may be contributed by the synergistic effect on downregulating ABCG2 expression in NCI-H460/TPT10 cells. To further verify the applicability of the NCI-H460/TPT10 cell line to test multidrug resistance (MDR) reversal agents in vivo and to evaluate the in vivo efficacy of CBZ on reversing TPT resistance, a tumor xenograft mouse model was established by implanting NCI-H460 and NCI-H460/TPT10 into nude mice. The NCI-H460/TPT10 xenograft tumors treated with the combination of TPT and CBZ dramatically reduced in size compared to tumors treated with TPT or CBZ alone. The TPT-resistant phenotype of NCI-H460/TPT10 cell line and the reversal capability of CBZ in NCI-H460/TPT10 cells could be extended from in vitro cell model to in vivo xenograft model. Collectively, CBZ is considered to be a potential approach in overcoming ABCG2-mediated MDR in NSCLC. The established NCI-H460/TPT10 xenograft model could be a sound clinically relevant resource for future drug screening to eradicate ABCG2-mediated MDR in NSCLC.

The efficacy of anti-cancer drugs in patients can be attenuated by the development of multi-drug resistance (MDR) due to ATP-binding cassette (ABC) transporters overexpression. In this in vitro study, we determined the reversal efficacy of the epidermal growth factor receptor (EFGR) inhibitor, saptinib, in SW620 and SW720/Ad300 colon cancer cells and HEK293/ABCB1 cells which overexpress the ABCB1 transporter. Sapitinib significantly increased the efficacy of paclitaxel and doxorubicin in ABCB1 overexpressing cells without altering the expression or the subcellular location of the ABCB1 transporter. Sapitinib significantly increased the accumulation of [3H]-paclitaxel in SW620/AD300 cells probably by stimulating ATPase activity which could competitively inhibit the uptake of [3H]-paclitaxel. Furthermore, sapitinib inhibited the growth of resistant multicellular tumor spheroids (MCTS). The docking study indicated that sapitinib interacted with the efflux site of ABCB1 transporter by π-π interaction and two hydrogen bonds. In conclusion, our study suggests that sapitinib surmounts MDR mediated by ABCB1 transporter in cancer cells.

Studies on host-pathogen interaction have identified human ACE2 as a host cell receptor responsible for mediating infection by coronavirus (COVID-19). Subsequent studies have shown striking difference of allele frequency among Europeans and Asians for a polymorphism rs2285666, present in ACE2. It has been revealed that the alternate allele (TT-plus strand or AA-minus strand) of rs2285666 elevate the expression level of this gene upto 50%, hence may play a significant role in SARS-CoV-2 susceptibility. Therefore, we have first looked the phylogenetic structure of rs2285666 derived haplotypes in worldwide populations and compared the spatial frequency of this particular allele with respect to the COVID-19 infection as well as case-fatality rate in India. For the first time, we ascertained a significant positive correlation for alternate allele (T or A) of rs2285666, with the lower infection as well as case-fatality rate among Indian populations. We trust that this information will be useful to understand the role of ACE2 in COVID-19 susceptibility.

Background/Aims: The overexpression of ATP-Binding Cassette (ABC) transporters has known to be one of the major obstacles impeding the success of chemotherapy in drug resistant cancers. In this study, we evaluated voruciclib, a CDK 4/6 inhibitor, for its chemo-sensitizing activity in ABCB1- and ABCG2- overexpressing cells. Methods: Cytotoxicity and reversal effect of voruciclib was determined by MTT assay. The intracellular accumulation and efflux of ABCB1 and ABCG2 substrates were measured by scintillation counter. The effects on expression and intracellular localization of ABCB1 and ABCG2 proteins were determined by Western blotting and immunofluorescence, respectively. Vanadate-sensitive ATPase assay was done to determine the effect of voruciclib on the ATPase activity of ABCB1 and ABCG2. Flow cytometric analysis was done to determine the effect of voruciclib on apoptosis of ABCB1 and ABCG2-overexpressing cells and docking analysis was done to determine the interaction of voruciclib with ABCB1 and ACBG2 protein. Results: Voruciclib significantly potentiated the effect of paclitaxel and doxorubicin in ABCB1-overexpressing cells, as well as mitoxantrone and SN-38 in ABCG2-overexpressing cells. Voruciclib moderately sensitized ABCC10- overexpressing cells to paclitaxel, whereas it did not alter the cytotoxicity of substrates of ABCC1. Furthermore, voruciclib increased the intracellular accumulation and decreased the efflux of substrate anti-cancer drugs from ABCB1- or ABCG2-overexpressing cells. However, voruciclib did not alter the expression or the sub-cellular localization of ABCB1 or ABCG2. Voruciclib stimulated the ATPase activity of both ABCB1 and ABCG2 in a concentration-dependent manner. Lastly, voruciclib exhibited a drug-induced apoptotic effect in ABCB1- or ABCG2- overexpressing cells. Conclusion: Voruciclib is currently a phase I clinical trial drug. Our findings strongly support its potential use in combination with conventional anti-cancer drugs for cancer chemotherapy.

Collective intelligence, an emergent phenomenon in which a composite system of multiple interacting agents performs at levels greater than the sum of its parts, has long compelled research efforts in social and behavioral sciences. To date, however, formal models of collective intelligence have lacked a plausible mathematical description of the relationship between local-scale interactions between autonomous sub-system components (individuals) and global-scale behavior of the composite system (the collective). In this paper we use the Active Inference Formulation (AIF), a framework for explaining the behavior of any non-equilibrium steady state system at any scale, to posit a minimal agent-based model that simulates the relationship between local individual-level interaction and collective intelligence. We explore the effects of providing baseline AIF agents (Model 1) with specific cognitive capabilities: Theory of Mind (Model 2), Goal Alignment (Model 3), and Theory of Mind with Goal Alignment (Model 4). These stepwise transitions in sophistication of cognitive ability are motivated by the types of advancements plausibly required for an AIF agent to persist and flourish in an environment populated by other highly autonomous AIF agents, and have also recently been shown to map naturally to canonical steps in human cognitive ability. Illustrative results show that stepwise cognitive transitions increase system performance by providing complementary mechanisms for alignment between agents’ local and global optima. Alignment emerges endogenously from the dynamics of interacting AIF agents themselves, rather than being imposed exogenously by incentives to agents’ behaviors (contra existing computational models of collective intelligence) or top-down priors for collective behavior (contra existing multiscale simulations of AIF). These results shed light on the types of generic information-theoretic patterns conducive to collective intelligence in human and other complex adaptive systems.

Multidrug resistance (MDR) is one of the leading causes of treatment failure in cancer chemotherapy. One major mechanism of MDR is the overexpressing of ABC transporters, whose inhibitors hold promising potential in antagonizing MDR. Glesatinib is a dual inhibitor of c-Met and SMO that is under phase II clinical trial for non-small cell lung cancer. In this work, we report the reversal effects of glesatinib to P-glycoprotein (P-gp) mediated MDR. Glesatinib can sensitize paclitaxel, doxorubicin, colchicine resistance to P-gp overexpressing KB-C2, SW620/Ad300, and P-gp transfected Hek293/ABCB1 cells, while has no effect to their corresponding parental cells and negative control drug cisplatin. Glesatinib suppressed the efflux function of P-gp to [3H]-paclitaxel and it didn't impact both the expression and cellular localization of P-gp based on Western blot and immunofluorescent analysis. Furthermore, glesatinib can stimulate ATPase in a dose-dependent manner. The docking study indicated that glesatinib interacted with human P-gp through several hydrogen bonds. Taken together, c-Met/SMO inhibitor glesatinib can antagonize P-gp mediated MDR by inhibiting its cell membrane transporting functions, suggesting new application in clinical trials.

Management of effort is one of the biggest challenges in any team, and is particularly difficult in distributed teams, where behavior is relatively invisible to teammates. Awareness systems, which provide real-time visual feedback about team members’ behavior, may serve as an effective intervention tool for mitigating various sources of process-loss in teams, including team effort. However, most of the research on visualization tools has been focusing on team communication and learning, and their impact on team effort and consequently team performance has been hardly studied. Furthermore, this line of research has rarely addressed the way visualization tool may interact with team composition, while comprehension of this interaction may facilitate a conceptualization of more effective interventions. In this article we review the research on feedback in distributed teams and integrate it with the research on awareness systems. Focusing on team effort, we examine the effect of an effort visualization tool on team performance in 72 geographically distributed virtual project teams. In addition, we test the moderating effect of team composition, specifically team members’ conscientiousness, on the effectiveness of the effort visualization tool. Our findings demonstrate that the effort visualization tool increases team effort and improves the performance in teams with a low proportion of highly conscientious members, but not in teams with a high proportion of highly conscientious members. We discuss the theoretical and practical implications of our findings, and suggest the need of future research to address the way technological advances may contribute to management and research of team processes.

Multidrug resistance is reported to be related to the transmembrane transportation of chemotherapeutic drugs by adenosine triphosphate-binding cassette (ABC) transporters. ABC subfamily G member 2 (ABCG2) is a member of the ABC transporter superfamily proteins, which have been implicated as a key contributor to the development of multidrug resistance in cancers. A new epigallocatechin gallate derivative, Y6 was synthesized in our group. Our previous study revealed that Y6 increased the sensitivity of drug-resistant cells to doxorubicin, which was associated with down-regulation of P-glycoprotein expression. In this study, we further determine whether Y6 could reverse ABCG2-mediated multidrug resistance. Results showed that, at non-toxic concentrations, Y6 significantly sensitized drug-selected non-small cell lung cancer cell line NCI-H460/MX20 to substrate anticancer drugs mitoxantrone, SN-38, and topotecan, and also sensitized ABCG2-transfected cell line HEK293/ABCG2-482-R2 to mitoxantrone and SN-38. Further study demonstrated that Y6 significantly increased the accumulation of [3H]-mitoxantrone in NCI-H460/MX20 cells by inhibiting the transport activity of ABCG2, without altering the expression levels and the subcellular localization of ABCG2. Furthermore, Y6 stimulated the adenosine triphosphatase activity with a concentration-dependent pattern under 20 μM in membranes overexpressing ABCG2. In addition, Y6 exhibited a strong interaction with the human ABCG2 transporter protein. Our findings indicate that Y6 may potentially be a novel reversal agent in ABCG2-positive drug-resistant cancers.

With the falling costs of solar arrays and battery storage and reduced reliability of the grid due to natural disasters, small-scale local generation and storage resources are beginning to proliferate. However, very few software options exist for integrated control of building loads, batteries and other distributed energy resources. The available software solutions on the market can force customers to adopt one particular ecosystem of products, thus limiting consumer choice, and are often incapable of operating independently of the grid during blackouts. In this paper, we present the “Solar+ Optimizer” (SPO), a control platform that provides demand flexibility, resiliency and reduced utility bills, built using open-source software. SPO employs Model Predictive Control (MPC) to produce real time optimal control strategies for the building loads and the distributed energy resources on site. SPO is designed to be vendor-agnostic, protocol-independent and resilient to loss of wide-area network connectivity. The software was evaluated in a real convenience store in northern California with on-site solar generation, battery storage and control of HVAC and commercial refrigeration loads. Preliminary tests showed price responsiveness of the building and cost savings of more than 10% in energy costs alone.

The main characteristic of tumor cell resistance is multidrug resistance (MDR). MDR is the principle cause of the decline in clinical efficacy of chemotherapeutic drugs. There are several mechanisms that could cause MDR. Among these, one of the most important mechanisms underlying MDR is the overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) super-family of transporters, which effectively pump out cytotoxic agents and targeted anticancer drugs across the cell membrane. In recent years, studies found that ABC transporters and tyrosine kinase inhibitors (TKIs) interact with each other. TKIs may behave as substrates or inhibitors depending on the expression of specific pumps, drug concentration, their affinity for the transporters and types of co-administered agents. Therefore, we performed in vitro experiments to observe whether olmutinib could reverse MDR in cancer cells overexpressing ABCB1, ABCG2, or ABCC1 transporters. The results showed that olmutinib at 3 μM significantly reversed drug resistance mediated by ABCG2, but not by ABCB1 and ABCC1, by antagonizing the drug efflux function in ABCG2-overexpressing cells. In addition, olmutinib at reversal concentration affected neither the protein expression level nor the localization of ABCG2. The results observed from the accumulation/efflux study of olmutinib showed that olmutinib reversed ABCG2-mediated MDR with an increasing intracellular drug accumulation due to inhibited drug efflux. We also had consistent results with the ATPase assay that olmutinib stimulated ATPase activity of ABCG2 up to 3.5-fold. Additionally, the molecular interaction between olmutinib and ABCG2 was identified by docking simulation. Olmutinib not only interacts directly with ABCG2 but also works as a competitive inhibitor of the transport protein. In conclusion, olmutinib could reverse ABCG2-mediated MDR. The reversal effect of olmutinib on ABCG2-mediated MDR cells is not due to ABCG2 expression or intracellular localization, but rather related to its interaction with ABCG2 protein resulting in drug efflux inhibition and ATPase stimulation.

Overexpression of ATP-binding cassette (ABC) transporters is one of the most important mechanisms responsible for multi-drug resistance (MDR). VS-4718, a tyrosine kinase inhibitor targeting focal adhesion kinase (FAK) with a potential anticancer effect, is currently evaluated in clinical trials. In this study, we investigated whether VS-4718 could reverse MDR mediated by ABC transporters, including ABCB1, ABCG2, and ABCC1. The results showed that VS-4718 significantly reversed ABCB1- and ABCG2-mediated MDR, but not MDR mediated by ABCC1. Treatment of VS-4718 did not alter the protein level and subcellular localization of ABCB1 or ABCG2. Mechanism studies indicated that the reversal effects of VS-4718 were related to attenuation of the efflux activity of ABCB1 and ABCG2 transporters. ATPase analysis indicated that VS-4718 stimulated the ATPase activity of ABCB1 and ABCG2. Docking study showed that VS-4718 interacted with the substrate-binding sites of both ABCB1 and ABCG2, suggesting that VS-4718 may affect the activity of ABCB1 and ABCG2 competitively. This study provided a novel insight for MDR cancer treatment. It indicated that combination of VS-4718 with antineoplastic drugs could attenuate MDR mediated by ABCB1 or ABCG2 in ABCB1- or ABCG2-overexpressing cancer cells.

Tyrosine kinases (TKs) play an important role in pathways that regulate cancer cell proliferation, apoptosis, angiogenesis and metastasis. Aberrant activity of TKs has been implicated in several types of cancers. In recent years, tyrosine kinase inhibitors (TKIs) have been developed to interfere with the activity of deregulated kinases. These TKIs are remarkably effective in the treatment of various human cancers including head and neck, gastric, prostate and breast cancer and several types of leukemia. However, these TKIs are transported out of the cell by ATP-binding cassette (ABC) transporters, resulting in development of a characteristic drug resistance phenotype in cancer patients. Interestingly, some of these TKIs also inhibit the ABC transporter mediated multi drug resistance (MDR) thereby; enhancing the efficacy of conventional chemotherapeutic drugs. This review discusses the clinically relevant TKIs and their interaction with ABC drug transporters in modulating MDR.

The triad of biomechanical preparation, pulp space sterilization and three-dimensional obturation is the hallmark of endodontic success. Complete disinfection of the pulp space cannot be achieved with most sophisticated instrumentation techniques. The role of irrigants in obtaining this goal cannot be underestimated. Optimal irrigation is based on the combined use of two or several irrigating solutions, in a specific sequence. Today’s irrigation armamentarium presents a diverse variety of tools and techniques that can assist the practitioner in reducing bacteria and debris within the canal system. However, currently there is no universally accepted standard irrigation technique. The aim of this article is to review armamentarium and various irrigants in endodontic practice.

In recent years, tyrosine kinase inhibitors (TKIs) have been shown capable of inhibiting the ATP-binding cassette (ABC) transporter-mediated multidrug resistance (MDR). In this study, we determine whether osimertinib, a novel selective, irreversible EGFR (epidermal growth factor receptor) TKI, could reverse ABC transporter-mediated MDR. The results showed that, at non-toxic concentrations, osimertinib significantly sensitized both ABCB1-transfected and drug-selected cell lines to substrate anticancer drugs colchicine, paclitaxel, and vincristine. Osimertinib significantly increased the accumulation of [3H]-paclitaxel in ABCB1 overexpressing cells by blocking the efflux function of ABCB1 transporter. In contrast, no significant alteration in the expression levels and localization pattern of ABCB1 was observed when ABCB1 overexpressing cells were exposed to 0.3 µM osimertinib for 72 h. In addition, ATPase assay showed osimertinib stimulated ABCB1 ATPase activity. Molecular docking and molecular dynamic simulations showed osimertinib has strong and stable interactions at the transmembrane domain of human homology ABCB1. Taken together, our findings suggest that osimertinib, a clinically-approved third-generation EGFR TKI, can reverse ABCB1-mediated MDR, which supports the combination therapy with osimertinib and ABCB1 substrates may potentially be a novel therapeutic stategy in ABCB1-positive drug resistant cancers.