Computational Exploration of Naturally Occurring Flavonoids as TGF-ß Inhibitors in Breast Cancer: Insights from Docking and Molecular Dynamics Simulations and In-vitro Cytotoxicity Study.

Breast cancer is a global health concern, demanding innovative treatments. Targeting the Transforming Growth Factor-beta (TGF-ß) signaling pathway, pivotal in breast cancer, is a promising approach. TGF-ß inhibits proliferation via G1 phase cell cycle arrest, acting as a suppressor initially, but in later stages, it promotes progression by enhancing motility, invasiveness, and metastasis formation. This study explores naturally occurring flavonoids' interactions with TGF-ß. Using molecular docking against the protein's crystal structure (PDB Id: 1PY5), Gossypin showed the highest docking score and underwent molecular dynamics simulation, revealing complex flexibility and explaining how flavonoids impede TGF-ß signaling in breast cancer. ADMET predictions adhered to Lipinski's rule of Five. Insights into flavonoid-TGF-ß binding offer a novel angle for breast cancer treatment. Flavonoids having a good docking score like gossypin, morin, luteolin and taxifolin shown potent cytotoxic effect on breast cancer cell line, MCF-7. Understanding these interactions could inspire flavonoid-based therapies targeting TGF-ß to halt breast cancer growth. These findings pave the way for personalized, targeted breast cancer therapies, offering hope against this formidable disease.

SHP-1 Protein Tyrosine Phosphatase Affects Early Postnatal Bone Development in Mice.

The Src homology region 2 domain-containing phosphatase-1 (SHP-1) is an intracellular tyrosine phosphatase that plays a negative regulatory role in immune cell signaling. Absent or diminished SHP-1 catalytic activity results in reduced bone mass with enhanced bone resorption. Here, we sought to investigate if Shp1 overexpression leads to increased bone mass and improved mechanical properties. Male and female wildtype (WT) and SHP1-transgenic (Tg) mice at 28, 56, and 84 days of age were compared. We applied microcomputed tomography to assess femoral cortical bone geometry and trabecular architecture and 3-point mechanical bending to assess mid-diaphyseal structural and estimated material properties. Serum OPG, RANKL, P1NP, and CTX-1 concentrations were measured by enzyme-linked immunoassay. The majority of transgene effects were restricted to the 28-day-old mice. Trabecular bone volume per total volume, trabecular number, and connectivity density were greater in 28-day-old female SHP1-Tg mice when compared to WTs. SHP1-Tg female mice showed increased total and medullary areas, with no difference in cortical area and thickness. Cortical tissue mineral density was strongly genotype-dependent. Failure load, yield load, ultimate stress, and yield stress were all lower in 28-day-old SHP1-Tg females. In 28-day-old SHP1-Tg females, circulating levels of OPG and P1NP were higher and RANKL levels were lower than WT controls. Our study demonstrates a role for SHP-1 in early postnatal bone development; SHP-1 overexpression negatively impacted whole bone strength and material properties in females.

Using the Health Belief Model to understand intention to vaccinate for Lyme disease in the United States.

AIMS: A growing number of Lyme disease (LD) cases in the U.S. are reported in states neighbouring those with high-incidence (>10 cases per 100,000 population) rates. Considering the evolving epidemiology, high-incidence counties in many of these "neighbouring states," and the forthcoming vaccines, understanding the drivers of vaccination intention is critical, particularly how drivers of intention in neighbouring states vary relative to regions currently classified as high incidence. This study uses the Health Belief Model (HBM) to determine the key drivers associated with vaccine intention for U.S. adults and caregivers of children residing in neighbouring states. METHODS AND RESULTS: Using an established panel with quotas for age, sex, race/ethnicity and urbanity, we surveyed 887 adults and 822 caregivers of children residing in U.S. neighbouring states. Survey items included measures of intention and HBM constructs, all of which were assessed using 5-point Likert scales. We subsequently used structural equation modelling to understand the influence of the HBM constructs on LD vaccine intention. Estimates from structural equation modelling show that the HBM constructs explain much of the variation in intention to vaccinate against LD. Intentions to vaccinate for both adults and caregivers are positively influenced by cues to action, perceived susceptibility of LD, and perceived benefits to vaccination. Both are also negatively influenced by perceived barriers to vaccination. The caregiver's intention to vaccinate is also positively influenced by the perceived severity of LD. CONCLUSION: The intention to vaccinate for respondents residing in LD neighbouring states is strongly influenced by recommendations from healthcare providers or the Centers for Disease Control and Prevention (CDC). As incidence rises in neighbouring states and the need to prevent disease becomes more overt, public health officials should strongly recognize the influence of healthcare providers and CDC recommendations on intention to vaccinate against LD.

A Superior Squeeze: Superior Vena Cava Syndrome Secondary to Small Cell Lung Cancer.

Superior vena cava (SVC) syndrome is an uncommon yet potentially fatal syndrome occurring after intrinsic or extrinsic compression to the SVC. While there are multiple emerging etiologies for this phenomenon, malignancy remains the most common. It is characterized by several symptoms including facial swelling, extremity swelling, shortness of breath, and headaches. We present the case of a 59-year-old female with a past medical history of cocaine abuse who was admitted for upper extremity swelling and facial edema. Imaging revealed a right suprahilar mass compressing a branch of the right pulmonary artery and SVC, in addition to bilateral segmental and subsegmental pulmonary emboli. She underwent an emergent biopsy and SVC stenting, with immunostaining revealing small cell lung cancer (SCLC). This case highlights a severe presentation of SVC syndrome caused by previously undetected SCLC.

Thrombus Tango: Hypercoagulable State With a Right Atrial Mass and Superimposed Persistent Bacteremia.

Bacillus cereus is an uncommon nosocomial bacteria, typically dismissed as a contaminant. This case is a unique scenario in which B. cereus bacteremia persisted despite appropriate treatment. Further investigation revealed the presence of a right atrial thrombus believed to harbor a biofilm responsible for the sustained bacteremia. Clearance of the thrombus using the AngioVac system (AngioDynamics, Inc., Latham, NY) led to the resolution of blood cultures, and subsequently, the patient was discharged with a six-week course of intravenous (IV) antibiotics.

Intention to vaccinate for Lyme disease using the Health Belief Model.

AIMS: Lyme disease (LD) cases in the United States are estimated to be approaching 500,000 annually. Protective measures, such as repellent use and wearing protective clothing are recommended by public health officials. However, no protective measure has been proven to be consistently effective, partly because they require consistent and persistent behaviour change. While safe and effective vaccines are in development, it is unclear what factors influence the intention to vaccinate against LD. This study uses the Health Belief Model (HBM) framework to determine key drivers associated with vaccine intention. The HBM is widely applied in public health research and uses the following constructs: perceived susceptibility and severity of disease, perceived benefits and barriers to disease prevention, and cues to action for disease prevention to predict health behaviours. To date, the HBM framework has not been applied to vaccination intention for LD. METHODS AND RESULTS: Data were collected from 874 adults and 834 caregivers of children residing in US states endemic to LD. Sampling adults and caregivers allows us to explore how the intention to vaccinate differs among those at-risk. Estimates from structural equation modelling (SEM) show that the HBM constructs explain much of the variation in intention to vaccinate against LD. Both adult and caregiver intentions to vaccinate are positively influenced by cues to action, perceived susceptibility of LD, and perceived benefits to vaccination. However, there is variation in the influence of constructs across the samples. Caregiver's intention to vaccinate is positively influenced by the perceived severity of LD and negatively influenced by safety concerns about the vaccine, whereas adult intention is negatively influenced by perceived barriers to vaccination. CONCLUSION: A strong relationship of cues to action on vaccine intention in samples of adults and caregivers suggests the importance of a recommendation from a healthcare provider or the Centers for Disease Control and Prevention (CDC).

The anti-HIV drug abacavir stimulates ß-catenin activity in osteoblast lineage cells.

Bone mineral density (BMD) loss in people living with HIV occurs with the initiation of combined antiretroviral therapy (cART), particularly with tenofovir disoproxil fumarate (TDF) containing cART. Switching from TDF to abacavir (ABC) or dolutegravir (DTG) leads to increased BMD. Whether BMD gains are due to cessation of TDF or anabolic effects of ABC or DTG is unclear. We investigated the effects of ABC and DTG on osteoblast lineage cells in vitro and in vivo. Primary human osteoblasts and male C57BL/6 mice were treated with individual antiretrovirals (ARVs) or a combination of ABC/DTG/lamivudine (3TC). Nearly all ARVs and cART inhibited osteogenic activity in vitro. Due to the importance of Wnt/ß-catenin in bone formation, we further investigated ARV effects on the Wnt/ß-catenin pathway. ABC, alone and as part of ABC/DTG/3TC, increased osteoblastic ß-catenin activity as indicated by increased TOPFlash activity, hypo-phosphorylated (active) ß-catenin staining, and ß-catenin targeted gene expression. Mice treated with TDF had decreased lumbar spine BMD and trabecular connectivity density in the vertebrae, while those treated with ABC/DTG/3TC reduced cortical area and thickness in the femur. Mice treated with ABC alone had no bone structural changes, increased circulating levels of the bone formation marker, P1NP, and elevated expression of the Wnt/ß-catenin target gene, Lef1, in osteocyte enriched samples. Further, bones from ARV-treated mice were isolated to evaluate ARV distribution. All ARVs were detected in the bone tissue, which was inclusive of bone marrow, but when bone marrow was removed, only TDF, ABC, and DTG were detected at ~0.1% of the circulating levels. Overall, our findings demonstrate that ABC activates Wnt/ß-catenin signaling, but whether this leads to increased bone formation requires further study. Assessing the impact of ARVs on bone is critical to informing ARV selection and/or discovery of regimens that do not negatively impact the skeleton.

Selection of Suitable Protein Structure from Protein Data Bank: An Important Step in Structure-based Drug Design Studies.

The selection of a protein structure is an important step for the success of the drug discovery process using structure-based design. Selection of the right crystal structure is critical as multiple crystal structures are available for the same protein in the Protein Data Bank (PDB). In this communication, we have discussed a systematic approach for selecting the right type of protein structure. Selecting crystal structures of TACE, 11ß-HSD1, DprE1, and SARS-CoV-2 Mpro enzymes for some case studies have been discussed for illustration.

Post-infectious headache: a reactive headache?

Post-infectious disease syndrome includes both neurological and non-neurological disorders. However, headache as an isolated or a presenting complaint of post-infectious illness has not been well acknowledged in the literature. In this retrospective observation, patients having daily headache of more than 1 week and <4 weeks duration were included. We divided this group into patients having headache with preceding history of febrile illness in the recent past and patients without such history of febrile illness. We compared clinical features and therapeutic responses of various drugs between the groups. There were no significant differences in demographic features in these groups. However, associated neck pain, nausea, photophobia and meningeal signs were more prevalent in patients having history of preceding infection. A relatively lower proportion of subjects showed complete response to drugs at 3 months in post-infectious group. Good responses were noted to steroids in post-infectious group. In conclusion, a subset of patients with daily headache may be because of post-infectious pathology and treatment in the early stage may prevent it from becoming chronic. Large prospective studies are required to confirm these observations.

Tau seeds are subject to aberrant modifications resulting in distinct signatures.

The prion-like spread of tau pathology could underlie a spectrum of clinical syndromes including Alzheimer's disease (AD). Although evidence indicates that tau is transmissible, it is unclear how pathogenic tau seeds are processed in neurons. Here, we analyze fibrillar wild-type and disease-associated P301L tau seeds by using in vitro and neuronal assays. We show that P301L seeds are uniquely modified by post-translational modifications (PTMs) within the microtubule-binding region (MTBR). Although these modifications do not alter tau seed trafficking or localization, acetylated tau variants show accelerated tau aggregation, enhanced tau PTM priming, and prion-like templating. To explain the enhanced tau seed acetylation, we demonstrate that P301L seeds undergo auto-acetylation. Moreover, tau acts generally to inhibit HDAC6 deacetylase activity by preventing HDAC6 phosphorylation, leading to increased substrate acetylation. Our study highlights complex post-translational regulation of transmissible tau seeds and provides insight into the biological properties of tau strains in AD and other tauopathies.

Extension of postharvest shelf-life in green bell pepper (Capsicum annuum L.) using exogenous application of polyamines (spermidine and putrescine).

To extend the postharvest shelf-life of green bell pepper (Capsicum annuum L.), an exogenous application of two polyamines, Spermidine and Putrescine (SPD-PUT), was tested in multiple combinations (10 µM plus 10 µM, 20 µM plus 20 µM, and 30 µM plus 30 µM) at 4 ±â€¯1 °C for 40 days. The titratable acidity, protein content, activities of catalase and peroxidase, chlorophyll and capsaicin content gradually decreased for all the treated and untreated fruits throughout the storage period. On the other hand, proline content and antioxidant 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radical scavenging activity continuously increased with the extension of time-span under storage. Among the three treatment combinations, the combination of 20 µM SPD and 20 µM PUT was found to be the optimum, based on the response of all the morphological and physicochemical traits assessed. The same combination was effective in sustaining the quality of green bell pepper following its harvest, for a period of at least 40 days.

Dry Needling-Induced Pneumothorax.

Dry needling is a widely used alternative therapy for musculoskeletal disorders, such as myofascial pain. The procedure involves placing a solid monofilament needle into myofascial trigger points or connective tissue to relieve pain. Some of the complications secondary to this procedure include cardiac tamponade, hematoma, infection, nerve injury, and pneumothorax. Although the incidence is low, the complications can be potentially life threatening. We present the case of a 44-year-old man who had dry needling of the infraspinatus, supraspinatus, rhomboid, and paraspinal muscles with subsequent development of a left apical pneumothorax. Given that the pneumothorax was small, the patient had good recovery with supplemental oxygen. Although the incidence of pneumothorax is very low, it is an important diagnosis to consider for a patient presenting with dry cough, malaise, chest pain, or shortness of breath after a dry needling procedure. Patients should be made aware of these potential complications as part of an informed consent.

Changes in antioxidant and biochemical activities in castor oil-coated Capsicum annuum L. during postharvest storage.

This study, for the first time, evaluates the efficiency of castor oil when used as an external coating on Capsicum annuum L., to increase postharvest storage-life at 4 ± 1 °C. The castor oil-coated fruits were successfully stored for 36 days, while the non-coated fruits could only sustain for 18 days. Throughout the storage period (at 9-day intervals), different antioxidants and biochemical assays (allied with storage) such as titratable acidity, ascorbic acid content, ferrous ion chelating activity, reducing power, DPPH scavenging activity, hydroxyl radical scavenging activity, total phenolic content, total sugar estimation, and enzymatic study of polyphenol oxidase and pectate lyase, were assessed. During storage, the castor oil-coated fruits showed a substantial decrease in titratable acidity, ascorbic acid content, total phenolic content, including antioxidant activities such as reducing power and DPPH activity; however, an increase in ferrous ion chelating activity, total soluble sugar content, polyphenol oxidase activity and initial pectate lyase activity was observed, in contrast to that of the non-coated fruits. The application of castor oil proved to be effective in delaying the ripening process of fruits during storage.

Continuous High-Frequency Oscillation Therapy in Invasively Ventilated Pediatric Subjects in the Critical Care Setting.

BACKGROUND: Continuous high-frequency oscillation (CHFO) creates a pressure gradient in the small airways that accelerates expiratory flow. The intended use of CHFO therapy is to facilitate secretion removal and treat atelectasis. Our objective was to assess the feasibility, safety, and efficacy of CHFO in the mechanically ventilated pediatric population. METHODS: After institutional review board approval, we retrospectively reviewed medical records of mechanically ventilated children treated with CHFO (the MetaNeb system) at our institution from July 1, 2007 through August 31, 2012. Patients supported with extracorporeal membrane oxygenation were excluded. We evaluated changes in ventilator settings in subjects with ventilator data documented within 6 h pre- and post-treatment. We evaluated arterial blood gas (ABG) results for individual treatments, comparing ABG results within 8 h pre-therapy to ABG results within 3 h post-treatment. Oxygen index and PaO2 /FIO2 were calculated. Demographic data, blood pressure, heart rate, and development of new air leak while being treated with CHFO were recorded. Pre- and post-CHFO measurements were compared using Wilcoxon signed-rank testing. RESULTS: Our cohort included 59 invasively ventilated subjects. Median age was 2 y (range 1 month to 19 y), and median weight was 14 kg (2-81 kg). We evaluated data on 528 total treatments (range per subject 1-39 treatments). Peak inspiratory pressure significantly decreased with CHFO, whereas other parameters, including PaCO2 and breathing frequency, remained stable. There was no significant change in systolic blood pressure, diastolic blood pressure, or heart rate following treatment with CHFO. One subject (2%) developed a clinically insignificant pneumothorax during CHFO. CONCLUSIONS: CHFO is feasible and seems safe in our cohort of mechanically ventilated pediatric subjects. The rate of pneumothorax was consistent with that seen in similar pediatric ICU populations. These preliminary results suggest that CHFO may be beneficial by improving lung compliance in pediatric subjects with secretion-induced atelectasis. Prospective clinical studies are needed to further evaluate the clinical efficacy and safety of CHFO in children receiving invasive mechanical ventilation.

Acute multiple cranial neuropathy: An oculopharyngeal variant of Guillain-Barré Syndrome.

We report the case of a 20-year-old male who presented to us with acute bilateral multiple cranial neuropathy in the form of bilateral total ophthalmoplegia and bulbar dysfunction. The patient had normal haematological and biochemical investigations, however, cerebrospinal fluid (CSF) analysis showed raised protein (96mg/dl) in the second week of illness. Peripheral nerve conduction studies and an MRI of the brain were normal. The patient showed gradual improvement after three weeks of supportive treatment. Considering the course of illness and the clinical and investigational profile, a diagnosis of an oculopharyngeal variant of Guillain-Barré syndrome (GBS) was made.

Awareness and Approach towards Hypertension Management among General Practitioners of Western Vadodara.

BACKGROUND: Hypertension (HTN) is a major risk factor contributing to premature mortality from cardiovascular and cerebrovascular disease.To decrease morbidity and mortality from HTN, timely diagnosis of the disease and its complications, urgent treatment and referrals are required. General Practioners (GPs) are the first tier of the health care system in India and have a wide scope of practice. It is important to know the awareness and approach of primary care physicians to hypertension in their daily practice as compared to standard practice recommendations and guidelines, to identify targets for improvements. With this objective we decided to interview them personally and analyse their approach. MATERIALS AND METHODS: We conducted a cross-sectional survey in 80 general practitioners (GPs) of the western part of Vadodara city with the use of a questionnaire prepared from JNC-7 guidelines and standard medical books. Seventy seven [97.55%] GPs completed the questionnaire and their responses were statistically analysed. RESULTS: Twenty percent of GPs were not applying BP cuff properly for BP measurement. Only 18% and 16.6 % could diagnose isolated diastolic hypertension (IDH) and isolated systolic hypertension respectively (ISH) and 21% and 29% would have considered treatment of IDH and ISH respectively.48% consider treating pre-hypertension using non-pharmacological measures. Only 21% use thiazide diuretics for uncomplicated HTN and 50% use beta-blockers in coronary artery disease patients. CONCLUSION: In our study, most of the GPs in western Vadodara are well aware and updated about the initial lab investigations,non-pharmacological measures and complications of HTN but lack an effective approach towards history taking for HTN,technique for measurement of blood pressure, diagnosis and treatment of IDH and ISH. Pre-hypertension and systolic and diastolic hypertension is under-treated and thiazide diuretics are underutilized. This study can be used to identify targets and approaches to improve hypertension management at the primary care level.

Comparison of sealing ability of MTA and EndoSequence Bioceramic Root Repair Material: a bacterial leakage study.

OBJECTIVE: To compare the sealing ability of ProRoot mineral trioxide aggregate (MTA) to the sealing ability of EndoSequence Bioceramic Root Repair Material (ES-BCRR) putty using a bacterial leakage model. METHOD AND MATERIALS: Root canals of 60 single-rooted extracted teeth were enlarged to an apical diameter of 0.5 mm using EndoSequence files. The apical 3 mm of each root was sectioned at 90 degrees to the long axis of the root. An ultrasonic surgical tip was used to prepare a 3-mm deep root-end preparation in all teeth. Teeth were equally divided into four groups: Group 1, MTA; Group 2, ES-BCRR putty; Group 3, positive control, gutta-percha without sealer; Group 4, negative control, sealed with wax and nail varnish. Prepared teeth were kept moist for 48 hours to allow for initial setting of the materials. After ethylene oxide sterilization, the teeth were suspended in sterilized vials containing 3% phenol lactose broth and inoculated with Enterococcus faecalis through the occlusal access openings. The samples were observed daily for leakage to a maximum of 28 days. Chi-square and Fisher exact tests were used to compare the experimental groups and an alpha level of significance was set at P = .05. RESULTS: In the ES-BCRR group 93% of samples leaked, compared to only 20% of samples in the MTA group. There was a significant difference in leakage between the experimental groups (P < .0001). Also there were no significant differences between the negative control group and MTA group and between the positive control group and ES-BCRR group (P = 1.00). CONCLUSION: Samples in the ES-BCRR group leaked significantly more than samples in the MTA group.