Screening of phytochemicals from Clerodendrum inerme (L.) Gaertn as potential anti-breast cancer compounds targeting EGFR: an in-silico approach.

Breast cancer (BC) is the most prevalent malignancy among women around the world. The epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor (RTK) of the ErbB/HER family. It is essential for triggering the cellular signaling cascades that control cell growth and survival. However, perturbations in EGFR signaling lead to cancer development and progression. Hence, EGFR is regarded as a prominent therapeutic target for breast cancer. Therefore, in the current investigation, EGFR was targeted with phytochemicals from Clerodendrum inerme (L.) Gaertn (C. inerme). A total of 121 phytochemicals identified by gas chromatography-mass spectrometry (GC-MS) analysis were screened against EGFR through molecular docking, ADMET analyses (Absorption, Distribution, Metabolism, Excretion, and Toxicity), PASS predictions, and molecular dynamics simulation, which revealed three potential hit compounds with CIDs 10586 [i.e. alpha-bisabolol (-6.4 kcal/mol)], 550281 [i.e. 2,(4,4-Trimethyl-3-hydroxymethyl-5a-(3-methyl-but-2-enyl)-cyclohexene) (-6.5 kcal/mol)], and 161271 [i.e. salvigenin (-7.4 kcal/mol)]. The FDA-approved drug gefitinib was used to compare the inhibitory effects of the phytochemicals. The top selected compounds exhibited good ADMET properties and obeyed Lipinski's rule of five (ROF). The molecular docking analysis showed that salvigenin was the best among the three compounds and formed bonds with the key residue Met 793. Furthermore, the molecular mechanics generalized born surface area (MMGBSA) calculations, molecular dynamics simulation, and normal mode analysis validated the binding affinity of the compounds and also revealed the strong stability and compactness of phytochemicals at the docked site. Additionally, DFT and DOS analyses were done to study the reactivity of the compounds and to further validate the selected phytochemicals. These results suggest that the identified phytochemicals possess high inhibitory potential against the target EGFR and can treat breast cancer. However, further in vitro and in vivo investigations are warranted towards the development of these constituents into novel anti-cancer drugs.Communicated by Ramaswamy H. Sarma.

Comparison of Postoperative Complications of Open Versus Laparoscopic Cholecystectomy According to the Modified Clavien-Dindo Classification System.

BACKGROUND: Though laparoscopic cholecystectomy has become a gold standard management technique for gallbladder diseases, an open approach can also be used for patients having complicated gallbladder disease. Post-cholecystectomy complications are well-documented in existing English scientific literature but are not well understood according to the grade of intervention required to treat those complications. OBJECTIVE: To compare the postoperative complications of laparoscopic versus open cholecystectomy according to the modified Clavien-Dindo classification (MCDC) system. MATERIALS AND METHODS:  A retrospective study was conducted at the Department of General Surgery, Unit - III, Lahore General Hospital, Lahore, comprising the data of patients operated between July 01, 2021, and December 31, 2021, after departmental approval # SU-III/73/LGH, dated April 1, 2022. Patients with the definitive diagnosis of acute cholecystitis, chronic cholecystitis, cholelithiasis, and cholecysto-duodenal fistula were included, while cases of choledocholithiasis and, gall bladder carcinoma were excluded from this study. Eighty patients met the inclusion criteria, with 40 patients in each group of open and laparoscopic cholecystectomy. Information for the data set of age, gender, history of surgical procedure, immediate and late outcome, length of surgery, and MCDC grade were collected. Low-grade complications were Grade I and Grade II, while Grades III to V were high-grade. RESULTS: The mean age of included patients was 42.52 ± 8.76 and 40.025 ± 8.12 years, in the open and laparoscopic group, with 80% and 90% female preponderance, respectively. Grade I and Grade II complications occurred in both groups of patients, with Grade III only in patients who underwent open cholecystectomy. None of the patients from each group developed Grade IV or Grade V complications. Among 40 patients who underwent laparoscopic cholecystectomy, 35% of the patients developed low-grade complications, whereas 40% of the patients developed low-grade complications after open cholecystectomy, with respiratory complications being the most common. High-grade complications after open cholecystectomy were found among 2.5% of patients, whereas no patients developed high-grade complications following the laparoscopic approach. CONCLUSION: Patients who underwent laparoscopic cholecystectomy are less prone to develop complications than patients undergoing open cholecystectomy, hence requiring low-grade interventions of surgical and non-surgical types. MCDC is a valuable tool for assessing surgical complications and can help improve patient outcomes by providing a standardized method for reporting and comparing complication rates.

Optimizing the number of variants tracked to follow disease burden with circulating tumor DNA assays in metastatic colorectal cancer.

Background: The number of somatic mutations detectable in circulating tumor DNA (ctDNA) is highly heterogeneous in metastatic colorectal cancer (mCRC). The optimal number of mutations required to assess disease kinetics is relevant and remains poorly understood. Objectives: To determine whether increasing panel breadth (the number of tracked variants in a ctDNA assay) would alter the sensitivity in detecting ctDNA in patients with mCRC. Design: We used archival tissue sequencing to perform an in silico assessment of the optimal number of tracked mutations to detect and monitor disease kinetics in mCRC using sequencing data from the Canadian Cancer Trials Group CO.26 trial. Methods: For each patient, 1, 2, 4, 8, 12, or 16 of the most clonal (highest variant allele frequency) somatic variants were selected from archival tissue-based whole-exome sequencing and assessed for the proportion of variants detected in matched ctDNA at baseline, week 8, and progression timepoints. Results: Data from 110 patients were analyzed. Genes most frequently encountered among the top four highest VAF variants in archival tissue were TP53 (51.9% of patients), APC (43.3%), KRAS (42.3%), and SMAD4 (9.6%). While the frequency of detecting at least one tracked variant increased when expanding beyond variant pool sizes of 1 and 2 in baseline (p = 0.0030) and progression (p = 0.0030) ctDNA samples, we observed no significant benefit to increases in variant pool size past four variants in any of the ctDNA timepoints (p < 0.05). Conclusion: While increasing panel breadth beyond two tracked variants improved variant re-detection in ctDNA samples from patients with treatment refractory mCRC, increases beyond four tracked variants yielded no significant improvement in variant re-detection.

Biologically inspired stealth - Camouflaged strategies in nanotechnology for the improved therapies in various diseases.

Nanotechnology has received increasing attention in the past decade and it's being used as a model for developing better treatments for a variety of diseases. Despite the fact that nanotechnology-based therapy has greatly improved treatment regimens, it still faces challenges such as inadequate circulation, insufficient accumulation at the target region, and undesired toxicity. In this regard, scientists are working on producing cell-membrane camouflaged nanoparticles as a biomimetic technique for modifying the surface of existing nanoparticles to produce significant therapeutic benefits following imparting myriad of desired functionalities. Membranes originating from erythrocytes, white blood cells, cancer cells, stem cells, platelets, or bacterial cells have been used to coat nanoparticle surfaces and create biologically inspired camouflaged nanoparticles. These biomemitic delivery systems have been proven to have potential applications in diagnosing and treating vaiorus diseases, including drug administration, immunisation, immunological regulation, and detoxification. From its inception to the present, we provide a complete description of this advanced technique for functionalizing nanoparticle surfaces. The method of making these membrane coated nanoparticles as well as their characterisation have been thoroughly discussed. Following that, we focused on the diversity of cell membranes derived from distinct cells in the evolution of nanoparticles, emphasising how these biologically inspired stealth - camouflaged techniques have led to increased therapeutic efficacy in a variety of disease states.

Antibiotic adjuvants: synergistic tool to combat multi-drug resistant pathogens.

The rise of multi-drug resistant (MDR) pathogens poses a significant challenge to the field of infectious disease treatment. To overcome this problem, novel strategies are being explored to enhance the effectiveness of antibiotics. Antibiotic adjuvants have emerged as a promising approach to combat MDR pathogens by acting synergistically with antibiotics. This review focuses on the role of antibiotic adjuvants as a synergistic tool in the fight against MDR pathogens. Adjuvants refer to compounds or agents that enhance the activity of antibiotics, either by potentiating their effects or by targeting the mechanisms of antibiotic resistance. The utilization of antibiotic adjuvants offers several advantages. Firstly, they can restore the effectiveness of existing antibiotics against resistant strains. Adjuvants can inhibit the mechanisms that confer resistance, making the pathogens susceptible to the action of antibiotics. Secondly, adjuvants can enhance the activity of antibiotics by improving their penetration into bacterial cells, increasing their stability, or inhibiting efflux pumps that expel antibiotics from bacterial cells. Various types of antibiotic adjuvants have been investigated, including efflux pump inhibitors, resistance-modifying agents, and compounds that disrupt bacterial biofilms. These adjuvants can act synergistically with antibiotics, resulting in increased antibacterial activity and overcoming resistance mechanisms. In conclusion, antibiotic adjuvants have the potential to revolutionize the treatment of MDR pathogens. By enhancing the efficacy of antibiotics, adjuvants offer a promising strategy to combat the growing threat of antibiotic resistance. Further research and development in this field are crucial to harness the full potential of antibiotic adjuvants and bring them closer to clinical application.

Deciphering the environmental impact on spike architectural traits for grain yield consolidation in bread wheat (T. aestivum L.).

The realization of grain yield in wheat is decided by source-sink balance under prevailing environmental conditions. Management conditions like changing the sowing time influence the source-sink capacity through modification in agronomic traits. Therefore, this experiment was conducted to decipher the influence of spike architectural traits (SATs) on grain yield and to open avenues for further grain yield enhancement. Comparatively early sowing over timely sowing gives the advantage of realizing higher grain yield with a positive relationship with SATs namely spike length, spikelets per spike, individual spike weight, individual grain weight, number of grains per spikelet, grain length, and grain width of upper and lower spike portion. Confirmatory factorial analysis revealed that spike length, spikelets per spike, individual spike weight, grains per spikelet were having a significant effect in deciding grain yield in early sown. The presence of a significant effect of genotype by environment interaction over grain yield and SATs allows the exploitation of available genotypic and environmental variability for further yield enhancement. GGE analysis on transformed and standardized grain yield-trait (GY-trait) combinations was used in the selection of genotypes having high GY-trait combinations for both sowing times. In early sowing, WG 11 was the best for high GY with high individual spike weight; grain length and grain width at lower and upper parts of the spike; and shorter days to 50% flowering. Genotypes exclusively having the high GY-trait combination along with low values of remaining GY-trait combinations were also selected with genotype focused GGE approach.

Effect of Combined Immune Checkpoint Inhibition vs Best Supportive Care Alone in Patients With Advanced Colorectal Cancer: The Canadian Cancer Trials Group CO.26 Study.

Importance: Single-agent immune checkpoint inhibition has not shown activities in advanced refractory colorectal cancer (CRC), other than in those patients who are microsatellite-instability high (MSI-H). Objective: To evaluate whether combining programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibition improved patient survival in metastatic refractory CRC. Design, Setting, and Participants: A randomized phase 2 study was conducted in 27 cancer centers across Canada between August 2016 and June 2017, and data were analyzed on October 18, 2018. Eligible patients had histologically confirmed adenocarcinoma of the colon or rectum; received all available standard systemic therapies (fluoropyrimidines, oxaliplatin, irinotecan, and bevacizumab if appropriate; cetuximab or panitumumab if RAS wild-type tumors; regorafenib if available); were aged 18 years or older; had adequate organ function; had Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease. Interventions: We randomly assigned patients to receive either 75 mg of tremelimumab every 28 days for the first 4 cycles plus 1500 mg durvalumab every 28 days, or best supportive care alone (BSC) in a 2:1 ratio. Main Outcomes and Measures: The primary end point was overall survival (OS) and a 2-sided P<.10 was considered statistically significant. Circulating cell-free DNA from baseline plasma was used to determine microsatellite instability (MSI) and tumor mutation burden (TMB). Results: Of 180 patients enrolled (121 men [67.2%] and 59 women [32.8%]; median [range] age, 65 [36-87] years), 179 were treated. With a median follow-up of 15.2 months, the median OS was 6.6 months for durvalumab and tremelimumab and 4.1 months for BSC (hazard ratio [HR], 0.72; 90% CI, 0.54-0.97; P = .07). Progression-free survival was 1.8 months and 1.9 months respectively (HR, 1.01; 90% CI, 0.76-1.34). Grade 3 or 4 adverse events were significantly more frequent with immunotherapy (75 [64%] patients in the treatment group had at least 1 grade 3 or higher adverse event vs 12 [20%] in the BSC group). Circulating cell-free DNA analysis was successful in 168 of 169 patients with available samples. In patients who were microsatellite stable (MSS), OS was significantly improved with durvalumab and tremelimumab (HR, 0.66; 90% CI, 0.49-0.89; P = .02). Patients who were MSS with plasma TMB of 28 variants per megabase or more (21% of MSS patients) had the greatest OS benefit (HR, 0.34; 90% CI, 0.18-0.63; P = .004). Conclusions and Relevance: This phase 2 study suggests that combined immune checkpoint inhibition with durvalumab plus tremelimumab may be associated with prolonged OS in patients with advanced refractory CRC. Elevated plasma TMB may select patients most likely to benefit from durvalumab and tremelimumab. Further confirmation studies are warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT02870920.

Traditional medicines of plant origin used for the treatment of inflammatory disorders in Pakistan: A review.

OBJECTIVE: To pool data on ethnobotanical medicine for the treatment of inflammatory disorders in Pakistan. METHODS: We reviewed 237 research publications based on data from the six provinces in Pakistan (Punjab = 85, Khyber Pakhtunkhwa = 65, Sindh = 15, Balochistan = 8, Gilgit Baltistan = 22, Azad Jammu and Kashmir = 42) published until June 2015 in various journals. This was achieved using seven online databases: ScienceDirect, Google, Google Scholar, PubMed, Wiley Online Library, SpringerLink, and MEDLINE. Data were analyzed from different perspectives. RESULTS: People from Pakistan made use of 371 plant species belonging to 263 genera and 99 families for the treatment of inflammatory disorders. Plants from the Asteraceae family were used most often. Herbs were the dominant growth form. Leaves were the plant parts used most often. Decoctions were the main preparation method. Nine plant species were used most frequently in the dwellers of most regions of Pakistan. A total of 111 plants were shown experimentally to have neither anti-arthritic nor anti-inflammatory activities, and 148 plant species were threatened. Eighty-four species had commercial importance. Twelve plant species were imported, and 25 plant species were exported, from Pakistan. CONCLUSION: This review provides baseline data for plant species in Pakistan that have potential anti-inflammatory/anti-arthritic activities.