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Background: Tele-rehabilitation programs have emerged as a promising approach to improve access to physiotherapy services for athletes with sports-related injuries. This randomized controlled trial aimed to compare the effectiveness of a tele-rehabilitation program with traditional in-person physiotherapy in improving outcomes for this population. Methods: This randomized controlled trial enrolled a large sample of 780 athletes with sports-related injuries to compare the effectiveness of tele-rehabilitation and traditional in-person physiotherapy. Blinding procedures were implemented to minimize bias. The intervention group received tele-rehabilitation physiotherapy, whereas the control group received traditional in-person physiotherapy. Pre- and post-intervention assessments were conducted to measure outcome measures, including range of motion, muscle strength, pain levels, and functional performance. Results: Significant improvements were observed in all outcome measures in both the tele-rehabilitation and in-person groups from baseline to postintervention. Independent t tests demonstrated no significant differences between the two groups in any of the outcome measures. These findings indicate that the tele-rehabilitation program was as effective as traditional in-person physiotherapy in improving the outcomes of athletes with sports-related injuries, even in a large sample size of 780 participants. Conclusion: This study provides robust evidence supporting the feasibility and effectiveness of tele-rehabilitation programs as viable alternatives to traditional in-person physiotherapy for athletes with sports-related injuries. These findings highlight the potential of tele-rehabilitation to significantly expand access to high-quality physiotherapy services for a large number of athletes. Further research should focus on evaluating the long-term effectiveness and cost-effectiveness of tele-rehabilitation programs in sports rehabilitation using larger sample sizes.
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Telerreabilitação , Humanos , Modalidades de FisioterapiaRESUMO
TP53 is the most frequently mutated tumor suppressor gene in many cancers, yet biochemical characterization of several of its reported mutations with probable biological significance have not been accomplished enough. Specifically, missense mutations in TP53 can contribute to tumorigenesis through gain-of-function of biochemical and biological properties that stimulate tumor growth. Here, we identified a relatively rare mutation leading to a proline to leucine substitution (P152L) in TP53 at the very end of its DNA-binding domain (DBD) in a sample from an Indian oral cancer patient. Although the P152Lp53 DBD alone bound to DNA, the full-length protein completely lacked binding ability at its cognate DNA motifs. Interestingly, P152Lp53 could efficiently tetramerize, and the mutation had only a limited impact on the structure and stability of full-length p53. Significantly, when we expressed this variant in a TP53-null cell line, it induced cell motility, proliferation, and invasion compared with a vector-only control. Also, enhanced tumorigenic potential was observed when P152Lp53-expressing cells were xenografted into nude mice. Investigating the effects of P152Lp53 expression on cellular pathways, we found that it is associated with up-regulation of several pathways, including cell-cell and cell-extracellular matrix signaling, epidermal growth factor receptor signaling, and Rho-GTPase signaling, commonly active in tumorigenesis and metastasis. Taken together, our findings provide a detailed account of the biochemical and cellular alterations associated with the cancer-associated P152Lp53 variant and establish it as a gain-of-function TP53 variant.
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Carcinogênese/genética , Proteína Supressora de Tumor p53/genética , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Mutação com Ganho de Função , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Invasividade Neoplásica/genética , Polimorfismo de Nucleotídeo Único , Transdução de Sinais/genética , Ativação Transcricional , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Androgen receptor (AR) signaling axis plays a vital role in the development of prostate and critical in the progression of prostate cancer. Androgen withdrawal initially regresses tumors but eventually develops into aggressive castration-resistant prostate cancer (CRPC). Activator Protein-1 (AP-1) transcription factors are most likely to be associated with malignant transformation in prostate cancer. Hence, to determine the implication of AR and AP-1 in promoting the transition of prostate cancer to the androgen-independent state, we used AR-positive LNCaP and AR-negative PC-3 cells as an in vitro model system. The effect of dihydrotestosterone or anti-androgen bicalutamide on the cell proliferation and viability was assessed by MTT assay. Expression studies on AR, marker genes-PSA, TMPRSS2, and different AP-1 factors were analyzed by semi-quantitative RT-PCR and expressions of AR and Fra-1 proteins were analyzed by Western blotting. Dihydrotestosterone induced the cell proliferation in LNCaP with no effect on PC-3 cells. Bicalutamide decreased the viability of both LNCaP and PC-3 cells. Dihydrotestosterone induced the expression of AR, PSA, c-Jun, and Fra-1 in LNCaP cells, and it was c-Jun and c-Fos in case of PC-3 cells, while bicalutamide decreased their expression. In addition, constitutive activation and non-regulation of Fra-1 by bicalutamide in PC-3 cells suggested that Fra-1, probably a key component, involved in transition of aggressive androgen-independent PC-3 cells with poor prognosis.
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Regulação Neoplásica da Expressão Gênica , Neoplasias de Próstata Resistentes à Castração/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Fator de Transcrição AP-1/metabolismo , Linhagem Celular Tumoral , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Proteínas Proto-Oncogênicas c-fos/genética , Fator de Transcrição AP-1/genéticaRESUMO
Steroid hormones and their nuclear receptors play a major role in the development and progression of breast cancer. MCF-7 cells are triple-positive breast cancer cells expressing estrogen receptor (ER), progesterone receptor (PR), and glucocorticoid receptor (GR). However, interaction and their role in expression pattern of activator protein (AP-1) transcription factors (TFs) are not completely understood. Hence, in our study, MCF-7 cells were used as an in vitro model system to study the interplay between the receptors and hormones. MCF-7 cells were treated with estradiol-17ß (E2), progesterone (P4), and dexamethasone (Dex), alone or in combination, to study the proliferation of cells and expression of AP-1 genes. MTT assay results show that E2 or P4 induced the cell proliferation by more than 35 %, and Dex decreased the proliferation by 26 %. E2 and P4 are found to increase ERα by more than twofold and c-Jun, c-Fos, and Fra-1 AP-1 TFs by more than 1.7-fold, while Dex shows opposite effect of E2- or P4-induced effect as well as effect on the expression of nuclear receptors and AP-1 factors. E2 antagonist Fulvestrant (ICI 182,780) found to reduce proliferation and E2-induced expression of AP1-TFs, while P4 or Dex antagonist Mifepristone (RU486) is found to block GR-mediated expression of NRs and AP-1 mRNAs. Results suggest that E2 and P4 act synergistically, and Dex acts as an antagonist of E2 and P4.
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Neoplasias da Mama/metabolismo , Proliferação de Células/efeitos dos fármacos , Receptor alfa de Estrogênio/metabolismo , Proteínas de Neoplasias/metabolismo , Receptores de Glucocorticoides/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Dexametasona/farmacologia , Estradiol/farmacologia , Receptor alfa de Estrogênio/agonistas , Receptor alfa de Estrogênio/genética , Feminino , Humanos , Células MCF-7 , Proteínas de Neoplasias/agonistas , Proteínas de Neoplasias/genética , Progesterona/farmacologia , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/genética , Receptores de Progesterona/agonistas , Receptores de Progesterona/genéticaRESUMO
Carbamazepine is an anticonvulsant medication commonly used to treat epilepsy and other neurological disorders. The purpose of this study was to assess the impact of carbamazepine on prenatal development, including maternal-fetal, external, visceral, and skeletal toxicity. Additionally, the study aimed to investigate the effects of orally administered Carbamazepine at a lower dose range in Wistar rats. Pregnant female rats were randomly distributed into control (G1) group administered with distilled water orally (n=8), low dose (G2) group administered at 25â¯mg/kg, intermediate dose (G3) group at 50â¯mg/kg, and high dose (G4) group at 100â¯mg/kg through oral gavage from gestation day (GD) 5-19. Pregnant female rats were scheduled to necropsy on gestation day (GD) 20. During the evaluation, the uterus was observed for number of live or viable fetuses, dead fetuses, early resorptions, late resorptions, number of corpora lutea and the sex ratio (m/f) per litter. Further, fetuses were subjected to materno-fetal examination which included observation for placenta, amniotic fluid, and umbilical cord followed by external evaluation. Additionally, half of the fetuses were subjected to visceral, craniofacial evaluation and other half of the fetuses were subjected to skeletal evaluation by double staining method using Alcian Blue for cartilages and Alizarin Red S for bones. It was observed that there was a significant decrease in the rate of pregnancy in the intermediate dose (G3) group and in high dose (G4) group when compared with the control group. Moreover, treatment with the Carbamazepine caused significant increase in fetal malformations such as dilation of lateral and third ventricle in brain, in intermediate dose (G3) group and high dose (G4) group when compared with the control (G1) group, dilation of ureters in high dose (G4) group. Fetal skeletal malformations like bent and nodulated ribs were also observed in intermediate dose (G3) group. Existing research substantially supports the claim that carbamazepine can cause teratogenic effects and prenatal development toxicity even at a lower dose range.
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Anticonvulsivantes , Carbamazepina , Ratos Wistar , Animais , Carbamazepina/toxicidade , Feminino , Gravidez , Anticonvulsivantes/toxicidade , Administração Oral , Desenvolvimento Fetal/efeitos dos fármacos , Anormalidades Induzidas por Medicamentos , Troca Materno-Fetal , Masculino , Desenvolvimento Embrionário/efeitos dos fármacos , RatosRESUMO
BACKGROUND: Musculoskeletal injuries, such as strains, are prevalent across all age groups and have a substantial impact on daily functioning and quality of life. OBJECTIVE: To examine the effectiveness of high-intensity interval training (HIIT) with traditional rehabilitation programs on pain, range of motion (ROM), muscular strength, and functional changes in promoting accelerated recovery from musculoskeletal injuries. METHODS: A total of 80 participants (54 males, 26 females; mean age 35.6 years) with various musculoskeletal injuries were randomly assigned to either the HIIT group (n= 40) or the traditional rehabilitation group (n= 40). The HIIT group underwent a six-week supervised program, with three sessions per week. The traditional rehabilitation group followed a similar six-week program emphasizing low to moderate intensity exercises and traditional rehabilitation techniques. Outcome measures, including pain levels, ROM, muscular strength, and functional outcomes, were assessed pre- and post-intervention. RESULTS: Significant improvements were observed in both the HIIT and traditional rehabilitation groups. However, the HIIT group demonstrated superior outcomes. Participants in the HIIT group experienced a greater reduction in pain levels compared to the traditional rehabilitation group (mean visual analog scale (VAS) score decrease of 5.2 vs. 3.8, respectively, p< 0.05). Functional outcomes significantly favored the HIIT group, with participants achieving faster completion times in the Timed Up and Go test (mean reduction of 2.1 seconds vs. 1.5 seconds, respectively, p< 0.01) and longer distances in the Single Leg Hop test (mean increase of 32 cm vs. 25 cm, respectively, p< 0.05). CONCLUSION: HIIT showed superior effectiveness over traditional rehabilitation in accelerating recovery from musculoskeletal injuries, with greater pain reduction and improved functional outcomes. Incorporating HIIT into rehabilitation protocols may offer an efficient approach for expedited recovery and enhanced functional capacity.
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Treinamento Intervalado de Alta Intensidade , Masculino , Feminino , Humanos , Adulto , Treinamento Intervalado de Alta Intensidade/métodos , Qualidade de Vida , Equilíbrio Postural , Estudos de Tempo e Movimento , DorRESUMO
Squalene (SQ) has been documented in the past for its ability to reduce inflammation, but its mechanism needs more information. In this study, we investigated squalene as an anti-inflammatory drug candidate and the framework involved in treating inflammation (INF) using the network pharmacology concept. The molecular targets of SQ and INF that are available in databases and the overlaps between these targets were demonstrated using InteractiVenn. The protein-protein networks were generated that in turn revealed several key targets and were further processed with Cytoscape. The gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) studies were performed. We also performed molecular docking tests that validated the binding affinity of molecular targets and drugs. A total of 100 SQ targets and 11,417 INF-related targets yielded 93 overlapping targets. Seven core targets, CRHR1, EGFR, ERBB2, HIF1A, SLC6A3, MAP2K1, and F2R were found to be relevant with respective to SQ's anti-inflammatory activity. The underlying mechanism of SQ with regard to INF was interpreted by analyzing various enrichment analyses along with the KEGG pathway. In conclusion, SQ played a vital role in the management of INF by regulating CRHR1, EGFR, ERBB2, HIF1A, SLC6A3, MAP2K1, and F2R. The research outcomes are crucial as they offer significant insights into the use of SQ for combating inflammation. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00217-0.
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Major research interests on quantum key distribution (QKD) are primarily focused on increasing 1. Point-to-point transmission distance (1000 km). 2. Secure key rate (Mbps). 3. Security of quantum layer (device-independence). It is great to push the boundaries in these fronts but these isolated approaches are neither scalable nor cost-effective due to requirements of specialised hardware and different infrastructure. Current and future QKD network requires addressing different set of challenges apart from distance, key rate and quantum security. In this regard, we present ChaQra-a sub quantum network with core features as 1. Crypto agility (integration in the already deployed telecommunication fibres). 2. Software defined networking (SDN paradigm for routing different nodes). 3. reliability (addressing denial-of-service with hybrid quantum safe cryptography). 4. upgradability (modules upgradation based on scientific and technological advancements). 5. Beyond QKD (using QKD network for distributed computing, multi-party computation etc). Our results demonstrate a clear path to create and accelerate quantum secure Indian subcontinent under national quantum mission.
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UNLABELLED: Geriatric dentistry or gerodontics is the delivery of dental care to older adults involving the diagnosis, prevention and treatment of problems associated with normal aging and age-related diseases as part of an interdisciplinary team with other health care professionals. AIM: To evaluate the oral mucosal status in the elderly population of different age group and fnd out the association of age, gender and denture with oral mucosal disorders. MATERIALS AND METHODS: The study sample consisted of 570 geriatric persons concentrating mainly on the oral mucosal changes or lesions occurring in the geriatric population. Individuals those are aged above 60 years were selected, and all the examined geriatric persons were categorized into 3 age groups to fnd out the association of oral mucosal lesions in each group. Group I-60 to 65 years, Group II-66 to 70 years, Group III-71 and above years. RESULTS: The sample of 570 elderly patients included 279 (48.95%) men and 291 (51.05%) women in three age groups: 61 to 65 years (40.35%), 66 to 70 years (31.05%), and 71 years and older (28.60%). The sample included 254 (44.56%) dentate patients, 205 (35.96%) denture wearers (partial and complete denture wearers) and 111 (19.47%) edentulous persons who lacked dentures in both the jaws. Almost half of the patients examined (48%) had one or more oral mucosal lesions. The 48% of the patients who presented with oral mucosal lesions, twenty fve different oral mucosal conditions were identifed and the three most common fndings were lingual varices (13.68%), denture induced infammatory fbrous hyperplasia (4.21%), squamous cell carcinoma (4.21%). There was some differences in the distribution of oral mucosal condition among the sexes. Leukoplakia and dysplasia were signifcantly associated with men (p < 0.001) whereas the association of fbroma and lichen planus with women were signifcant (p < 0.001). CONCLUSION: In our study it was found that patients in groups II and III had more prevalence of oral mucosal disorders. Lingual varices, oral squamous cell carcinoma, fbroma and denture induced infammatory fbrous hyperplasia were more commonly associated with the geriatric patients. The oral lesions (fbroma and lichen planus) were strongly associated with women while leukoplakia was strongly associated with men. Ageing is an important factor that can infuence the occurrence of mucosal lesions and with age the oral mucosa becomes more permeable to noxious substances and more vulnerable to external carcinogens.
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Avaliação Geriátrica/estatística & dados numéricos , Doenças da Boca/epidemiologia , Idoso , Carcinoma de Células Escamosas/epidemiologia , Dentição , Prótese Total/estatística & dados numéricos , Prótese Parcial/estatística & dados numéricos , Feminino , Fibroma/epidemiologia , Fibrose , Humanos , Hiperplasia , Índia/epidemiologia , Leucoplasia Oral/epidemiologia , Líquen Plano Bucal/epidemiologia , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/epidemiologia , Boca Edêntula/epidemiologia , Lesões Pré-Cancerosas/epidemiologia , Fatores Sexuais , Estomatite sob Prótese/epidemiologia , Língua/irrigação sanguínea , Varizes/epidemiologiaRESUMO
Artificial intelligence (AI) techniques have the potential to revolutionize drug release modeling, optimize therapy for personalized medicine, and minimize side effects. By applying AI algorithms, researchers can predict drug release profiles, incorporate patient-specific factors, and optimize dosage regimens to achieve tailored and effective therapies. This AI-based approach has the potential to improve treatment outcomes, enhance patient satisfaction, and advance the field of pharmaceutical sciences. International collaborations and professional organizations play vital roles in establishing guidelines and best practices for data collection and sharing. Open data initiatives can enhance transparency and scientific progress, facilitating algorithm validation.
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Multi-coloured and white-light emissions from pyrene-based hydrazones are described. They exhibit excitation wavelength-dependent emissions in solution due to the suppression of Kasha's rule. Interestingly, in dimethylformamide, 1-3 emit light that covers all the regions of primary colours as a function of excitation wavelength, and 1 and 2 emit white light (λex = 420 nm) in isopropanol.
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Posting of visual data in the social network has now become a common trend. Mainly, users are posting selfies or facial images over the social media that depict various moods at different instances. This has attracted the attention of researchers to come up with facial expression mining from social media images. Aim of the present work is to improve the performance of emotion analysis in a more efficient way in terms of accuracy and reliability. Developing new strategies for carrying out emotion analysis on posts containing images in social media. In this work, a novel model has been presented that focuses on transformed features for the purpose. Six distinct sentimental emotion classes (labeled 0 through 5) are considered in this work. They are 0: Sad, 1: Fear, 2: Awful, 3: Happy, 4: Surprised, 5: Satisfied. This model consists of three major stages: Feature extraction, Feature selection, and Class labeling.â¢This work incorporates the use of 2D Ortho-normal Stockwell Transformation (DOST) method is used for feature extraction of facial images.â¢Following the feature extraction model, feature selection is implemented through 'bi-variate t-test'.â¢Finally, these selected features are subjected to a AdaBoost based Random Forest classifier for Emotion Classification(ARFEC) for the purpose of class labeling towards different classes of expression. The Flickr8k, CK+ and FER2013 image databases are utilized for validating the efficiency of the developed ARFEC model. Analysis of results shows the effectiveness of ARFEC model with overall rates of accuracy of 89.5 %, 92.5 % and 89.5 % respectively for the databases taken. Performance of ARFEC model when compared with other existing methods such as Support Vector Machine and K-Nearest Neighbors yielded better results in terms of overall rate of accuracy.
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Dually targeting the epigenetic proteins lysine specific demethylase 1 (LSD1) and histone deacetylases (HDACs) that play a key role in cancer cells by modulating gene repressor complexes including CoREST will have a profound effect in inhibiting tumour growth. Here, we evaluated JBI-097 a dual LSD1/HDAC6 inhibitor, for its in vitro and in vivo activities in various tumor models. In vitro, JBI-097 showed a strong potency in inhibiting LSD1 and HDAC6 enzymatic activities with the isoform selectivity over other HDACs. Cell-based experiments demonstrated a superior anti-proliferative profile against haematological and solid tumor cell lines. JBI-097 also showed strong modulation of HDAC6 and LSD1 specific biomarkers, alpha-tubulin, CD86, CD11b, and GFi1b. In vivo, JBI-097 showed a stronger effect in erythroleukemia, multiple myeloma xenograft models, and in CT-26 syngeneic model. JBI-097 also showed efficacy as monotherapy and additive or synergistic efficacy in combination with the standard of care or with immune checkpoint inhibitors. These and other findings suggest that JBI-097 could be a promising molecule for targeting the LSD1 and HDAC6. Further studies are warranted to elucidate the mechanism of action.
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Histona Desacetilases , Neoplasias , Humanos , Linhagem Celular Tumoral , Histona Desacetilases/metabolismo , Histona Desmetilases/genética , Neoplasias/tratamento farmacológico , Desacetilase 6 de HistonaRESUMO
Background: Urinary tract infections (UTI) are the most prevalent bacterial infection in humans. The uropathogenic E. coli (UPEC) expresses a range of virulence factors that contribute to their pathogenicity . The emergence of multidrug resistance (MDR)-associated UTI is increasing. This study monitors the distribution of virulence factors among UPEC strains to note the antibiogram, outcome and type of associated UTI. Methods: A prospective cross-sectional time-bound study of six months was done on clinically significant urinary isolates of Escherichia coli. Detection of haemolysin production and serum resistance was done by phenotypic methods. Genotypic characterization of the virulence genes ( papC, iutA, hlyA, cnf1) was done by multiplex PCR. Demographic data, clinical history, antibiogram and type of UTI was collected from clinical case records. Results:75 E.coli isolates from patients with suspected UTIs were included. Females had a higher preponderance of UTI (66.7%). 93% of patients were adults and the remaining 7% were from paediatrics. 24 (32%) isolates showed haemolysis by plate haemolysis and all isolates were serum-resistant. Out of 75 isolates, 65 were positive for at least one of four targeted genes, while remaining ten isolates were negative for all four genes. Multidrug resistance was found in 40 (53.3%) isolates. 97.4% of the UTI cases had a favourable clinical outcome at discharge. Mortality due to urosepsis was 2.6%. Conclusion: Association of hemolysin production with resistance to imipenem and norfloxacin in UPEC strains was significant. Presence of hlyA gene is positively associated with ceftazidime resistance. Nitrofurantoin, piperacillin, tazobactam, and cefaperazone sulbactam are possible candidates for empirical therapy of UTIs. Drugs like aminoglycosides, carbapenems and fosfomycin may be used as reserve drugs in the treatment of MDR-UTI. However, inappropriate usage can increase antibiotic resistance. Hence proper selection of antibiotics in hospitals taking into account the local antibiogram is needed to reduce the emergence of antibiotic resistance.
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Infecções por Escherichia coli , Infecções Urinárias , Escherichia coli Uropatogênica , Adulto , Feminino , Humanos , Criança , Fatores de Virulência/genética , Escherichia coli Uropatogênica/genética , Infecções por Escherichia coli/microbiologia , Centros de Atenção Terciária , Estudos Transversais , Hemólise , Estudos Prospectivos , Antibacterianos/uso terapêutico , Infecções Urinárias/tratamento farmacológico , Resistência Microbiana a MedicamentosRESUMO
The aim of the present study was to determine whether the serum ferritin, the biomarker of an acute phase reactant and the gall bladder wall edema, an early indicator of capillary leakage can predict the severity of dengue fever. This study included 131 patients, who were between the age group of 18-80 years. The patients presented to our department with an acute illness, within the first four days of high temperature. The statistical analysis of this study was performed by using the Chi-square and independent Student's t tests. The diagnostic markers are considered statistically significant, if the serum ferritin level is higher than 500 ng/ml and the gall bladder wall thickness is more than 3 mm. The present study observed that, 39 patients (89%) who had severe dengue (n = 44) revealed a significant gall bladder wall thickening, and this correlation was significant statistically (p < 0.000). It was also observed that, the ferritin levels have a highly significant positive correlation with the severity of dengue. The severe dengue patients had a mean ferritin level of 9125.34 µg/l, whereas the non-severe group had 4271 µg/l. This comparison was also statistically significant, as the p value was 0.003. We report that the serum ferritin levels have a highly significant positive correlation with the severity of dengue. The gall bladder wall edema during the third and fourth day of the illness was also associated with severe dengue. However, diffuse gall bladder wall thickening and high serum ferritin levels are also reported in various other conditions and their exact cause have to be determined by the correlation of associated clinical findings and imaging features.
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Neutrophils are closely involved in the regulation of tumor progression and formation of premetastatic niches. However, the mechanisms of their involvement and therapeutic regulation of these processes remain elusive. Here, we report a critical role of neutrophil peptidylarginine deiminase 4 (PAD4) in neutrophil migration in cancer. In several transplantable and genetically engineered mouse models, tumor growth was accompanied by significantly elevated enzymatic activity of neutrophil PAD4. Targeted deletion of PAD4 in neutrophils markedly decreased the intratumoral abundance of neutrophils and led to delayed growth of primary tumors and dramatically reduced lung metastases. PAD4-mediated neutrophil accumulation by regulating the expression of the major chemokine receptor CXCR2. PAD4 expression and activity as well as CXCR2 expression were significantly upregulated in neutrophils from patients with lung and colon cancers compared with healthy donors, and PAD4 and CXCR2 expression were positively correlated in neutrophils from patients with cancer. In tumor-bearing mice, pharmacologic inhibition of PAD4 with the novel PAD4 isoform-selective small molecule inhibitor JBI-589 resulted in reduced CXCR2 expression and blocked neutrophil chemotaxis. In mouse tumor models, targeted deletion of PAD4 in neutrophils or pharmacologic inhibition of PAD4 with JBI-589 reduced both primary tumor growth and lung metastases and substantially enhanced the effect of immune checkpoint inhibitors. Taken together, these results suggest a therapeutic potential of targeting PAD4 in cancer. SIGNIFICANCE: PAD4 regulates tumor progression by promoting neutrophil migration and can be targeted with a small molecule inhibitor to suppress tumor growth and metastasis and increase efficacy of immune checkpoint blockade therapy.
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Armadilhas Extracelulares , Neoplasias Pulmonares , Animais , Modelos Animais de Doenças , Armadilhas Extracelulares/metabolismo , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares/patologia , Camundongos , Neutrófilos , Proteína-Arginina Desiminase do Tipo 4 , Receptores de Quimiocinas/metabolismoRESUMO
PURPOSE: To investigate association of two single nucleotide polymorphisms (SNPs) ABCB1(rs1045462) and DRD3(rs6280) with clozapine response and the dose in treatment resistant schizophrenia (TRS) patients. METHODS: 200 TRS patients were enrolled in the study during their follow up visit post clozapine initiation. SNP assessment was performed for DRD3 (rs6280) and ABCB1(rs1045462) by sequencing. Blood sample for genotyping was collected with disease and treatment related variables recording on case record form. Patients were classified as responders or nonresponders based upon Andreasen criteria and Positive and Negative Syndrome Scale (PANSS). RESULTS: Mean clozapine dose, the genotype frequency distribution of ABCB1, DRD3 SNPs were significantly different in clozapine responder and non-responder study population (p < 0.05). CT genotype of ABCB1 and AG genotype of DRD3 were observed to be more prevalent in the responder group. TT genotype of ABCB1 and AG genotype of DRD3 were prevalent in the nonresponder group. Clozapine dosing equations for responder and nonresponder TRS populations were developed through logistic regression analysis. 27% variability in clozapine dose was explained by possible combinations of ABCB1 and DRD3 SNP analysis. CONCLUSION: Differential ABCB1(rs1045462) and DRD3(rs6280) genotype frequencies among the clozapine responders and non-responders explained clear feasibility of response predictor potential along with clozapine dose variability association. Pharmacogenetically guided clozapine dosing is possible if more SNPs are considered together with ABCB1(rs1045462) and DRD3(rs6280) in TRS patients.
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Antipsicóticos/administração & dosagem , Clozapina/administração & dosagem , Avaliação de Resultados em Cuidados de Saúde , Farmacogenética , Receptores de Dopamina D3/genética , Esquizofrenia/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , Idoso , Biomarcadores , Estudos Transversais , Feminino , Humanos , Índia/etnologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico , Esquizofrenia/etnologia , Esquizofrenia/fisiopatologia , Adulto JovemRESUMO
BACKGROUND: Secondary peritonitis, following intestinal perforation, constitutes a significant proportion of cases admitted as a surgical emergency and has a mortality rate of 6-21% worldwide. As a part of an antimicrobial stewardship program, we noted considerable variation among the choice of empirical regimens among such cases. Hence, we conducted a prospective study to generate the evidence for a rational empiric regimen for patients with secondary peritonitis following intestinal perforation. METHODS: The study included a complete follow up of 77 cases of secondary peritonitis admitted during a 12 month period. The intraoperative fluid (peritoneal) sample of the patient was sent for culture and sensitivity pattern analysis. RESULTS: The sites of perforation as seen in decreasing order were lower gastrointestinal (GI) (50.6%), upper GI (36.4%), and unclassified (13%). The most common organism found in the intraoperative fluid was Escherichia coli (47.9%) followed by Klebsiella pneumoniae (12.5%). amikacin, cefoperazone-sulbactam, piperacillin-tazobactam and imipenem were sensitive in 22 (out of 23 tested), 5 (out of 9), 13 (out of 13) and 22 (out of 22) isolates of E. coli and 3 (out of 6), 1 (out of 3), 4 (out of 6), 4 (out of 6) isolates of K. pneumoniae, respectively. The most common empirical antibiotic was cefoperazone-sulbactam (38.7%) followed by piperacillin-tazobactam (29.3%). CONCLUSION: Based on our prospective study, piperacillin-tazobactam or imipenem should be used empirically in patients presenting with complicated intra-abdominal infections secondary to perforated viscus, especially if they have sepsis or septic shock.
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CONTEXT: Cheiloscopy and dactyloscopy, both are well-established forensic tools used in individual identification in any scenario be it a crime scene or civil cause. Like finger prints, lip prints are unique and distinguishable for every individual. But their relationship to personality types has not been established excepting the hypothesis stating that finger prints could explain these personality patterns. AIMS: The study was aimed to record and correlate the lip and finger prints with that of character/personality of a person. SETTINGS AND DESIGN: The lip and finger prints and character of a person were recorded and the data obtained was subjected for statistical analysis, especially for Pearson's Chi-square test and correlation/association between the groups was also studied. MATERIALS AND METHODS: The study sample comprised of 200 subjects, 100 males and 100 females, aged between 18 and 30 years. For recording lip prints, brown/pink-colored lipstick was applied on the lips and the subjects were asked to spread uniformly over the lips. Lip prints were traced in the normal rest position on a plain white bond paper. For recording the finger prints, imprints of the fingers were taken on a plain white bond paper using ink pad. The collected prints were visualized using magnifying lens. To record the character of person, a pro forma manual for multivariable personality inventory by Dr. BC Muthayya was used. STATISTICAL ANALYSIS USED: Data obtained was subjected for statistical analysis, especially for Pearson's Chi-square test and correlation/association between the groups was also studied. RESULTS: In males, predominant lip pattern recorded was Type I with whorls-type finger pattern and the character being ego ideal, pessimism, introvert, and dogmatic; whereas in females, predominant lip pattern recorded was Type II with loops-type finger pattern and the character being neurotic, need achievers, and dominant. CONCLUSION: Many studies on lip pattern, finger pattern, palatal rugae, etc., for individual identification and gender determination exist, but correlative studies are scanty. This is the first study done on correlating patterns, that is, lip and finger pattern with the character of a person. With this study we conclude that this correlation can be used as an adjunct in the investigatory process in forensic sciences.