Nonsynonymous mutations in VEGF receptor binding domain alter the efficacy of bevacizumab treatment.

Vascular endothelial growth factor (VEGF) mediated angiogenesis is crucial for tumor progression. Isoforms of VEGF bind to different VEGF receptors (VEGFRs) to initiate angiogenesis specific cellular signaling. Inhibitors that target both the receptors and ligands are in clinical use to impede angiogenesis. Bevacizumab, a monoclonal antibody (mAb) approved by the Food and Drug Administration (FDA), binds in the VEGF receptor binding domain (RBD) of all soluble isoforms of VEGF and inhibits the VEGF-VEGFR interaction. Bevacizumab is also used in combination with other chemotherapeutic agents for a better therapeutic outcome. Understanding the intricate polymorphic character of VEGFA gene and the influence of missense or nonsynonymous mutations in the form of nonsynonymous polymorphisms (nsSNPs) on RBD of VEGF may aid in increasing the efficacy of this drug. This study has identified 18 potential nsSNPs in VEGFA gene that affect the VEGF RBD structure and alter its binding pattern to bevacizumab. The mutated RBDs, modeled using trRosetta, in addition to the changed pattern of secondary structure, post translational modification and stability compared to the wild type, have shown contrasting binding affinity and molecular interaction pattern with bevacizumab. Molecular docking analysis by ClusPro and visualization using PyMol and PDBsum tools have detected 17 nsSNPs with decreased binding affinity to bevacizumab and therefore may impact the treatment efficacy. Whereas VEGF RBD expressed due to rs1267535717 (R229H) nsSNP of VEGFA has increased affinity to the mAb. This study suggests that genetic characterization of VEGFA before bevacizumab mediated cancer treatment is essential in predicting the appropriate efficacy of the drug, as the treatment efficiency may vary at individual level.

Non-synonymous Single Nucleotide Polymorphisms in Human ACE2 Gene May Affect the Infectivity of SARS-CoV-2 Omicron Subvariants.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the coronavirus disease 2019 (COVID-19), which first appeared in December 2019. Angiotensin I converting enzyme 2 (ACE2) receptor, present on the host cells, interacts with the receptor binding domain (RBD) of spike (S) protein of SARS-CoV-2 and facilitates the viral entry into host cells. METHODS: Non-synonymous single nucleotide polymorphisms (nsSNPs) in the ACE2 gene may have an impact on the protein's stability and its function. The deleterious or harmful nsSNPs of the ACE2 gene that can change the strength as well as the pattern of interaction with the RBD of S protein were selected for this study. RESULTS: The ACE2:RBD interactions were analyzed by protein-protein docking study. The missense mutations A242V, R708W, G405E, D292N, Y633C, F308L, and G405E in ACE2 receptor were found to interact with RBD of Omicron subvariants with stronger binding affinity. Among the other selected nsSNPs of human ACE2 (hACE2), R768W, Y654S, F588S, R710C, R710C, A191P, and R710C were found to have lower binding affinity for RBD of Omicron subvariants. CONCLUSION: The findings of this study suggest that the nsSNPs present in the human ACE2 gene alter the structure and function of the protein and, consequently, the susceptibility to Omicron subvariants.

Tanshinone IIA targeting cell signaling pathways: a plausible paradigm for cancer therapy.

Natural compounds originating from plants offer a wide range of pharmacological potential and have traditionally been used to treat a wide range of diseases including cancer. Tanshinone IIA (Tan IIA), a bioactive molecule found in the roots of the Traditional Chinese Medicine (TCM) herb Salvia miltiorrhiza, has been shown to have remarkable anticancer properties through several mechanisms, such as inhibition of tumor cell growth and proliferation, metastasis, invasion, and angiogenesis, as well as induction of apoptosis and autophagy. It has demonstrated excellent anticancer efficacy against cell lines from breast, cervical, colorectal, gastric, lung, and prostate cancer by modulating multiple signaling pathways including PI3K/Akt, JAK/STAT, IGF-1R, and Bcl-2-Caspase pathways. This review focuses on the role of Tan IIA in the treatment of various cancers, as well as the underlying molecular mechanisms.

Evaluating the transmission feasibility of SARS-CoV-2 Omicron (B.1.1.529) variant to 143 mammalian hosts: insights from S protein RBD and host ACE2 interaction studies.

In comparison to previously known severe respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, the newly emerged Omicron (B.1.1.529) variant shows higher infectivity in humans. Exceptionally high infectivity of this variant raises concern of its possible transmission via other intermediate hosts. The SARS-CoV-2 infectivity is established via the association of spike (S) protein receptor binding domain (RBD) with host angiotensin I converting enzyme 2 (hACE2) receptor. In the course of this study, we investigated the interaction between Omicron S protein RBD with the ACE2 receptor of 143 mammalian hosts including human by protein-protein interaction analysis. The goal of this study was to forecast the likelihood that the virus may infect other mammalian species that coexist with or are close to humans in the household, rural, agricultural, or zoological environments. The Omicron RBD was found to interact with higher binding affinity with the ACE2 receptor of 122 mammalian hosts via different amino acid residues from the human ACE2 (hACE2). The rat (Rattus rattus) ACE2 was found to show the strongest interaction with Omicron RBD with a binding affinity of -1393.6 kcal/mol. These distinct strong binding affinity of RBD of Omicron with host ACE2 indicates a greater potential of new host transmissibility and infection via intermediate hosts. Though expected but the phylogenetic position of the mammalian species may not dictate the Omicron RBD binding to the host ACE2 receptor suggesting an involvement of multiple factors in guiding host divergence of the variant.

Nanomedicine-based immunotherapy for Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease caused by the deposition of amyloid ß (Aß) fibrils forming extracellular plaques and the development of neurofibrillary tangles (NFT) of intracellular hyperphosphorylated tau protein. Currently, the AD treatments focus on improving cognitive and behavioral symptoms and have limited success. It is imperative to develop novel treatment approaches that can control/inhibit AD progression, especially in the elderly population. Immunotherapy provides a promising and safe treatment option for AD by boosting the patient's immune system. The minimum immune surveillance in the immune-privileged brain, however, makes immunotherapy for AD a challenging endeavor. Therefore, the success of AD immunotherapy depends mainly on the strategy by which therapeutics is delivered to the brain rather than its efficacy. The blood-brain barrier (BBB) is a major obstacle to therapeutic delivery into the brain microenvironment. Various nano-formulations have been exploited to improve the efficacy of AD immunotherapy. In this review, the applications of different types of nano-formulations in augmenting AD immunotherapy have been discussed.

Analysis of the Compositional Features and Codon Usage Pattern of Genes Involved in Human Autophagy.

Autophagy plays an intricate role in paradigmatic human pathologies such as cancer, and neurodegenerative, cardiovascular, and autoimmune disorders. Autophagy regulation is performed by a set of autophagy-related (ATG) genes, first recognized in yeast genome and subsequently identified in other species, including humans. Several other genes have been identified to be involved in the process of autophagy either directly or indirectly. Studying the codon usage bias (CUB) of genes is crucial for understanding their genome biology and molecular evolution. Here, we examined the usage pattern of nucleotide and synonymous codons and the influence of evolutionary forces in genes involved in human autophagy. The coding sequences (CDS) of the protein coding human autophagy genes were retrieved from the NCBI nucleotide database and analyzed using various web tools and software to understand their nucleotide composition and codon usage pattern. The effective number of codons (ENC) in all genes involved in human autophagy ranges between 33.26 and 54.6 with a mean value of 45.05, indicating an overall low CUB. The nucleotide composition analysis of the autophagy genes revealed that the genes were marginally rich in GC content that significantly influenced the codon usage pattern. The relative synonymous codon usage (RSCU) revealed 3 over-represented and 10 under-represented codons. Both natural selection and mutational pressure were the key forces influencing the codon usage pattern of the genes involved in human autophagy.

Analyzing the interaction of human ACE2 and RBD of spike protein of SARS-CoV-2 in perspective of Omicron variant.

The newly identified Omicron (B.1.1.529) variant of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has steered concerns across the world due to the possession of a large number of mutations leading to high infectivity and vaccine escape potential. The Omicron variant houses 32 mutations in spike (S) protein alone. The viral infectivity is determined mainly by the ability of S protein Receptor Binding Domain (RBD) to bind to the human Angiotensin I Converting Enzyme 2 (hACE2) receptor. In this paper, the interaction of the RBDs of SARS-CoV-2 variants with hACE2 was analyzed by using protein-protein docking and compared with the novel Omicron variant. Our findings reveal that the Omicron RBD interacts strongly with hACE2 receptor via unique amino acid residues as compared to the Wuhan and many other variants. However, the interacting residues of RBD are found to be the same in Lamda (C.37) variant. This unique binding of Omicron RBD with hACE2 suggests an increased potential of infectivity and vaccine evasion potential of the new variant. The evolutionary drive of the SARS-CoV-2 may not be exclusively driven by RBD variants but surely provides for the platform for emergence of new variants.

Association of high mortality with extended-spectrum ß-lactamase (ESBL) positive cultures in community acquired infections.

PURPOSE: Infections due to multidrug resistant organisms have become a serious health concern worldwide. The present study was conducted to investigate the spectrum of microbial resistance pattern in the community and their effects on mortality. METHODS: A retrospective review and analysis of prospectively collected data was done of all patients admitted with diagnosis of sepsis in two tertiary care ICU's for a period of two years. Demographics, culture positivity, microbial spectrum, resistance pattern and outcome data were collected. RESULTS: Out of 5309 patients enrolled; 3822 had suspected clinical infection on admission with 1452 patients growing positive microbial cultures. Among these, 201 bacterial strains were isolated from patients who had community acquired infections. 73% were Gram negative bacilli, commonest being E. coli (63%). 63.4% E. coli and 60.7% Klebsiella isolates were ESBL producers. The mortality in ESBL positive infections was significantly higher as compared to ESBL negative infections (Odds ratio 2.756). Moreover, ESBL positive patients empirically treated with Beta Lactams+Beta Lactamase inhibitors (BL+BLI) had significantly higher mortality as compared to patients treated with carbapenems. More data from multiple centres need to be gathered to formulate appropriate antibiotic policy for critically ill patients admitted from the community.

Comparative evaluation of Airtraq™ optical Laryngoscope and Miller's blade in paediatric patients undergoing elective surgery requiring tracheal intubation: A randomized, controlled trial.

BACKGROUND AND AIMS: The Airtraq™ optical laryngoscope is the only marketed videolaryngoscope for paediatric patients besides the fibre-optic bronchoscope. We hypothesized that intubation would be easier with Airtraq™ compared to Miller blade. Hence, we compared Airtraq™ with the Miller laryngoscope as intubation devices in paediatric patients. METHODS: This prospective, randomized study was conducted in a tertiary care teaching hospital. Sixty children belonging to American Society of Anesthesiologists' Grade I-II, aged 2-10 years, posted for routine surgery requiring tracheal intubation were randomly allocated to undergo intubation using a Miller (n = 30) or Airtraq™ (n = 30) laryngoscope. The primary outcome measure was time of intubation. We also measured ease of intubation, number of attempts, percentage of glottic opening score (POGO), haemodynamic changes and airway trauma. Student t test was used to analyse parametric data. RESULTS: Intubation time was comparable between Miller's laryngoscope (15.13 ± 1.33s) compared to Airtraq™ (11.53 ± 0.49 s) (P = 0.29) The number of first and second attempts at intubation were 25 and 5 for the Miller laryngoscope and 29 and 1 for the Airtraq™. Median visual analogue score (VAS) for ease of intubation was 5 in Miller group compared to 3 in Airtraq™ group. The median POGO score was 75 in the Miller group and 100 in the Airtraq™ group (P = 0.01). Haemodynamic changes were maximum and most significant immediately and 1 min after intubation. Airway trauma occurred in three patients (9.09%) in Miller group and one patient (3.33%) in Airtraq™ group. CONCLUSION: The Airtraq™ reduced the difficulty of tracheal intubation and degree of haemodynamic stimulation compared to the Miller laryngoscope in paediatric patients.

A comparative study of three methods of ProSeal laryngeal mask airway insertion in children with simulated difficult laryngoscopy using a rigid neck collar.

BACKGROUND: Combined introducer tool and stylet technique of ProSeal laryngeal mask airway (PLMA) insertion was compared with the conventional digital manipulation and introducer tool technique in children with a rigid neck collar. METHODS: This was a randomized, single blinded, prospective study. Ninety ASA Grade I-II children weighing 10-20 kg were randomly allocated for PLMA insertion using the digital, introducer tool (IT) or combined IT and stylet techniques. Each group contained 30 patients. Difficult laryngoscopy was simulated using a rigid neck collar. The laryngoscopic view was graded prior to PLMA insertion. The digital and IT techniques were performed according to the manufacturer's instructions. The combined technique involved attaching the IT to the PLMA and inserting a flexible stylet through the drain tube. RESULTS: The median Cormack and Lehane grade was 2 in all three groups. Insertion was more frequently successful with the combined technique at the first attempt (combined 100%, digital 65.38%, IT 66.67%; p < 0.05), but success after three attempts was similar (combined 100%, digital 86.67%, IT 90%; p > 0.05). The time taken for successful placement was similar among groups at the first attempt, but was shorter for the combined technique for overall attempts (combined 18.33 ± 1.27 seconds, digital 27.85 ± 9.05 seconds, IT 26.89 ± 7.17 seconds; p < 0.05). There was no difference in postoperative airway morbidity. CONCLUSION: PLMA insertion with combined IT and stylet technique was more frequently successful than the digital or IT technique in pediatric patients without cervical spine motion.

Comparison of i-gel™ supraglottic device with classic laryngeal mask airway in anesthetized paralyzed children undergoing elective surgery.

CONTEXT: The newest variation of the i-gel supraglottic airway is a pediatric version. AIMS: This study was designed to investigate the usefulness of the size 2 i-gel compared with the classic laryngeal mask airway (cLMA) of the same size in anesthetized, paralyzed children. SETTINGS AND DESIGN: A prospective, randomized, single-blinded study was conducted in tertiary care teaching hospital. SUBJECT AND METHODS: Sixty ASA grade I-II patients undergoing lower abdominal, inguinal, and orthopedic surgery were included in this prospective study. The patients were randomly assigned to i-gel and cLMA groups (30 patients in each group). Size 2 supraglottic airway was inserted according to the assigned group. We assessed ease of insertion, hemodynamic data, oropharyngeal sealing pressure, and postoperative complications. STATISTICAL ANALYSIS USED: Parametric data were analyzed with the unpaired t-test and non-parametric data were analyzed with the Chi-square test. Unless otherwise stated, data are presented as mean (SD). Significance was taken as P < 0.05. RESULTS: There were no differences in the demographic and hemodynamic data among the two groups. The airway leak pressure of the i-gel group (26.1 ± 2.4 cm H2O) was significantly higher than that of the cLMA group (22.64 ± 2.2 cm H2O). The success rates for first attempt of insertion were similar among the two devices. There were no differences in the incidence of postoperative airway morbidity among the two groups. CONCLUSIONS: Hemodynamic parameters, ease of insertion, and postoperative complications were comparable between the i-gel and cLMA groups, but airway sealing pressure was significantly higher in i-gel group.