A Benzimidazole-Based N-Heterocyclic Carbene Derivative Exhibits Potent Antiproliferative and Apoptotic Effects against Colorectal Cancer.

Background and Objectives: Colorectal cancer (CRC) remains a major global health issue. Although chemotherapy is the first-line treatment, its effectiveness is limited due to drug resistance developed in CRC. To overcome resistance and improve the prognosis of CRC patients, investigating new therapeutic approaches is necessary. Materials and Methods: Using human colorectal adenocarcinoma (HT29) and metastatic CRC (SW620) cell lines, the potential anticancer properties of a newly synthesized compound 1-(Isobutyl)-3-(4-methylbenzyl) benzimidazolium chloride (IMBZC) were evaluated by performing MTT cytotoxicity, cell migration, and colony formation assays, as well as by monitoring apoptosis-related protein and gene expression using Western blot and reverse transcription-quantitative polymerase chain reaction technologies. Results: Tested at various concentrations, the half-maximal inhibitory concentrations (IC50) of IMBZC on HT29 and SW620 cell growth were determined to be 22.13 µM (6.97 µg/mL) and 15.53 µM (4.89 µg/mL), respectively. IMBZC did not alter the cell growth of normal HEK293 cell lines. In addition, IMBZC inhibited cell migration and significantly decreased colony formation, suggesting its promising role in suppressing cancer metastasis. Mechanistic analyses revealed that IMBZC treatment increased the expression of pro-apoptotic proteins p53 and Bax, while decreasing the expression of anti-apoptotic proteins Bcl-2 and Bcl-xL, thus indicating the induction of apoptosis in IMBZC-treated CRC cells, compared to untreated cells. Additionally, the addition of IMBZC to conventional chemotherapeutic drugs (i.e., 5-fluorouracil, irinotecan, and oxaliplatin) resulted in an increase in the cytotoxic potential of the drugs. Conclusions: This study suggests that IMBZC has substantial anticancer effects against CRC cells through its ability to induce apoptosis, inhibit cancer cell migration and colony formation, and enhance the cytotoxic effects of conventional chemotherapeutic drugs. These findings indicate that IMBZC could be a promising chemotherapeutic drug for the treatment of CRC. Further research should be conducted using in vivo models to confirm the anti-CRC activities of IMBZC.

Identification of 2-(N-aryl-1,2,3-triazol-4-yl) quinoline derivatives as antitubercular agents endowed with InhA inhibitory activity.

The spread of drug-resistant tuberculosis strains has become a significant economic burden globally. To tackle this challenge, there is a need to develop new drugs that target specific mycobacterial enzymes. Among these enzymes, InhA, which is crucial for the survival of Mycobacterium tuberculosis, is a key target for drug development. Herein, 24 compounds were synthesized by merging 4-carboxyquinoline with triazole motifs. These molecules were then tested for their effectiveness against different strains of tuberculosis, including M. bovis BCG, M. tuberculosis, and M. abscessus. Additionally, their ability to inhibit the InhA enzyme was also evaluated. Several molecules showed potential as inhibitors of M. tuberculosis. Compound 5n displayed the highest efficacy with a MIC value of 12.5 µg/mL. Compounds 5g, 5i, and 5n exhibited inhibitory effects on InhA. Notably, 5n showed significant activity compared to the reference drug Isoniazid. Molecular docking analysis revealed interactions between these molecules and their target enzyme. Additionally, the molecular dynamic simulations confirmed the stability of the complexes formed by quinoline-triazole conjugate 5n with the InhA. Finally, 5n underwent in silico analysis to predict its ADME characteristics. These findings provide promising insights for developing novel small compounds that are safe and effective for the global fight against tuberculosis.

Unveiling the potential of isatin-grafted phenyl-1,2,3-triazole derivatives as dual VEGFR-2/STAT-3 inhibitors: Design, synthesis and biological assessments.

The use of VEGFR-2 inhibitors as a stand-alone treatment has proven to be ineffective in clinical trials due to the robustness of cellular response loops that lead to treatment resistance when only targeting VEGFR-2. The over-activation of the signal transducer/activator of transcription 3 (STAT-3) is expected to significantly impact treatment failure and resistance to VEGFR-2 inhibitors. In this study, we propose the concept of combined inhibition of VEGFR-2 and STAT-3 to combat induced STAT-3-mediated resistance to VEGFR-2 inhibition therapy. To explore this, we synthesized new isatin-grafted phenyl-1,2,3-triazole derivatives "6a-n" and "9a-f". Screening on PANC1 and PC3 cancer cell lines revealed that compounds 6b, 6 k, 9c, and 9f exhibited sub-micromolar ranges. The most promising molecules, 6b, 6 k, 9c, and 9f, demonstrated the highest inhibition when tested as dual inhibitors on VEGFR-2 (with IC50 range 53-82 nM, respectively) and STAT-3 (with IC50 range 5.63-10.25 nM). In particular, triazole 9f showed the best results towards both targets. Inspired by these findings, we investigated whether 9f has the ability to trigger apoptosis in prostate cancer PC3 cells via the assessment of the expression levels of the apoptotic markers Caspase-8, Bcl-2, Bax, and Caspase-9. Treatment of the PC3 cells with compound 9f significantly inhibited the protein expression levels of VEGFR-2 and STAT-3 kinases compared to the control.

What Is the Value Proposition of Evidence-Based Guidelines? An Application of the Operative Value Index for Lumbar Fusions.

BACKGROUND: Elective lumbar fusions have received criticism for inappropriate utilization. Here, we use a novel Operative Value Index (OVI) to assess whether "indicated," evidence-based lumbar fusions are associated with increased value (outcomes per dollar spent). METHODS: This study is a retrospective analysis of a prospective observational cohort of 294 patients undergoing elective lumbar fusions at a single large academic institution. All patients were preoperatively evaluated by a panel of neurosurgeons for concordance with evidence-based medicine (EBM), determined through guidelines from the North American Spine Society. Oswestry Disability Index (ODI) scores were collected for all patients both preoperatively and at 6-months postoperatively. Time-driven activity-based costing was employed to determine both direct and indirect intraoperative costs. The OVI was defined as the percent improvement in ODI per $1000 spent intraoperatively. Generalized linear mixed model regression, adjusting for confounders, was performed to assess whether EBM-concordant surgeries were associated with higher OVI. RESULTS: Of 294 elective lumbar fusions, 92.9% (n = 273) were EBM-concordant. The average total cost of an EBM-concordant lumbar fusion was $17,932 (supplies: $13,020; personnel: $4314), compared to $20,616 (supplies: $15,467; personnel: $4758) for an EBM-discordant fusion. Average OVI was 2.27 for a concordant fusion, compared to 0.11 for a discordant fusion. Generalized linear mixed model analysis revealed that EBM-concordant cases were associated with significantly higher OVI (ß-coefficient 2.0, P < 0.001). CONCLUSIONS: EBM-concordant fusions were associated with 2% greater improvement in ODI scores from baseline for every $1000 spent intraoperatively. Systematic methods for increasing guideline adherence for lumbar fusions could therefore improve value at scale.

Label-Free Quantitative Proteomics of Oral Microbial Communities.

The oral cavity is a habitat for different microorganisms, of which bacteria are best described. Studying different bacterial taxa and their proteins is crucial to understanding their interactions with the host and other microbes. Also, for bacteria with virulence potential, identifying novel antigenic proteins is essential to finding candidates for the development of vaccines.Here, a workflow for gel-free and label-free protein analysis of oral bacterial species grown in vitro as a biofilm and a planktonic culture is described. Details on cultivation, protein extraction and digestion, peptide cleanup, LC-MS/MS run parameters, and subsequent bioinformatics analysis are included. Challenging steps in the workflow, such as growing different types of bacteria and selecting a suitable protein database, are also discussed. This protocol provides a valuable guide for metaproteomic experiments using multi-species models of oral bacteria.

How Do the True Intraoperative Costs of Endoscopic Diskectomy Compare With Microdiskectomy for Lumbar Disk Herniations? A Time-Driven Activity-Based Cost Analysis.

BACKGROUND AND OBJECTIVES: Endoscopic lumbar diskectomy (ED) is a minimally invasive option for addressing lumbar disk herniations. With the introduction of value-based care systems, assessing the true cost of certain procedures is critical when creating reimbursement models and comparing procedures. Here, we compared the costs of performing a microdiskectomy (MD) and ED using time-driven activity-based costing. METHODS: Total cost for the intraoperative episode was calculated using time-driven activity-based costing methodology. Individual costs were obtained by direct observation and electronic medical records and through querying multiple departments (business operations, sterile processing, plant operations, and pharmacy). Timestamps for all involved personnel and material resources were documented. A retrospective analysis was performed on 202 patients who underwent lumbar diskectomy through either MD (n = 167) or ED (n = 35) from 2018 to 2022. Personnel cost was calculated by multiplying the cost per unit time for each personnel type by the length of time spent in the operating room. Supply cost was calculated by aggregating the cost of all individual supplies, from medications to consumables to surgical trays, used during the case. Univariate and multivariable regression analyses were performed comparing the costs between these procedures. RESULTS: The average intraoperative cost per case for ED and MD was $3915 ± $1025 and $3162 ± $954, respectively. Multivariable regression analysis revealed that ED had higher total cost (ß-coefficient: $912 ± $281, P = <.01) and supply cost (ß-coefficient: $474 ± $155, P = <.01) than MD. When accounting for surgeon as a covariate, however, total cost (P = .478) and supply cost (P = .468) differences between ED and MD were negligible. CONCLUSION: ED has shown to be a better value option in addressing lumbar disk herniations, mostly because of advantages in perioperative care. Here, we show that when correcting for surgeon-level effects, the cost between the two procedures is statistically insignificant, reaffirming the value provided by ED.

Regulation of chloroplast biogenesis, development, and signaling by endogenous and exogenous cues.

Chloroplasts are one of the defining features in most plants, primarily known for their unique property to carry out photosynthesis. Besides this, chloroplasts are also associated with hormone and metabolite productions. For this, biogenesis and development of chloroplast are required to be synchronized with the seedling growth to corroborate the maximum rate of photosynthesis following the emergence of seedlings. Chloroplast biogenesis and development are dependent on the signaling to and from the chloroplast, which are in turn regulated by several endogenous and exogenous cues. Light and hormones play a crucial role in chloroplast maturation and development. Chloroplast signaling involves a coordinated two-way connection between the chloroplast and nucleus, termed retrograde and anterograde signaling, respectively. Anterograde and retrograde signaling are involved in regulation at the transcriptional level and downstream modifications and are modulated by several metabolic and external cues. The communication between chloroplast and nucleus is essential for plants to develop strategies to cope with various stresses including high light or high heat. In this review, we have summarized several aspects of chloroplast development and its regulation through the interplay of various external and internal factors. We have also discussed the involvement of chloroplasts as sensors of various external environment stress factors including high light and temperature, and communicate via a series of retrograde signals to the nucleus, thus playing an essential role in plants' abiotic stress response.

Do Busier Surgeons Have Lower Intraoperative Costs? An Analysis of Anterior Cervical Discectomy and Fusion Using Time-Driven Activity-Based Costing.

STUDY DESIGN: The present study is a single-center, retrospective cohort study of patients undergoing neurosurgical anterior cervical discectomy and fusion (ACDF). OBJECTIVE: Our objective was to use time-driven activity-based costing (TDABC) methodology to determine whether surgeons' case volume influenced the true intraoperative costs of ACDFs performed at our institution. SUMMARY OF BACKGROUND DATA: Successful participation in emerging reimbursement models, such as bundled payments, requires an understanding of true intraoperative costs, as well as the modifiable drivers of those costs. Certain surgeons may have cost profiles that are favorable for these "at-risk" reimbursement models, while other surgeons may not. METHODS: Total cost was divided into direct and indirect costs. Individual costs were obtained by direct observation, electronic medical records, and through querying multiple departments (business operations, sterile processing, plant operations, and pharmacy). Timestamps for all involved personnel and material resources were documented. All surgeons performing ACDFs at our primary and affiliated hospital sites from 2017 to 2022 were divided into four volume-based cohorts: 1-9 cases (n=10 surgeons, 38 cases), 10-29 cases (n=7 surgeons, 126 cases), 30-100 cases (n=3 surgeons, 234 cases), and > 100 cases (n=2 surgeons, 561 cases). RESULTS: The average total intraoperative cost per case was $7,116 +/- $2,945. The major cost contributors were supply cost ($4,444, 62.5%) and personnel cost ($2,417, 34.0%). A generalized linear mixed model utilizing Poisson distribution was performed with the surgeon as a random effect. Surgeons performing 1-9 total cases, 10-29 cases, and 30-100 cases had increased total cost of surgery (P < 0.001; P < 0.001; and P<0.001, respectively) compared to high-volume surgeons (> 100 cases). Among all volume cohorts, high-volume surgeons also had the lowest mean supply cost, personnel cost, and operative times, while the opposite was true for the lowest-volume surgeons (1-9 cases). CONCLUSION: It is becoming increasingly important for hospitals to identify modifiable sources of variation in cost. We demonstrate a novel use of TDABC for this purpose. LEVEL OF EVIDENCE: Level-III.

Discovery and Mechanistic Studies of Dual-Target Hits for Carbonic Anhydrase IX and VEGFR-2 as Potential Agents for Solid Tumors: X-ray, In Vitro, In Vivo, and In Silico Investigations of Coumarin-Based Thiazoles.

A dual-targeting approach is predicted to yield better cancer therapy outcomes. Consequently, a series of coumarin-based thiazoles (5a-h, 6, and 7a-e) were designed and constructed as potential carbonic anhydrase (CA) and VEGFR-2 suppressors. The inhibitory actions of the target compounds were assessed against CA isoforms IX and VEGFR-2. The assay results showed that coumarin-based thiazoles 5a, 5d, and 5e can effectively inhibit both targets. 5a, 5d, and 5e cytotoxic effects were tested on pancreatic, breast, and prostate cancer cells (PANC1, MCF7, and PC3). Further mechanistic investigation disclosed the ability of 5e to interrupt the PANC1 cell progression in the S stage by triggering the apoptotic cascade, as seen by increased levels of caspases 3, 9, and BAX, alongside the Bcl-2 decline. Moreover, the in vivo efficacy of compound 5e as an antitumor agent was evaluated. Also, molecular docking and dynamics displayed distinctive interactions between 5e and CA IX and VEGFR-2 binding pockets.

What is the Marginal Cost of Using Robot Assistance or Navigation for Transforaminal Lumbar Interbody Fusion? A Time-Driven Activity-Based Cost Analysis.

BACKGROUND AND OBJECTIVE: Our primary objective was to compare the marginal intraoperative cost of 3 different methods for pedicle screw placement as part of transforaminal lumbar interbody fusions (TLIFs). Specifically, we used time-driven activity-based costing to compare costs between robot-assisted TLIF (RA-TLIF), TLIF with intraoperative navigation (ION-TLIF), and freehand (non-navigated, nonrobotic) TLIF. METHODS: Total cost was divided into direct and indirect costs. We identified all instances of RA-TLIF (n = 20), ION-TLIF (n = 59), and freehand TLIF (n = 233) from 2020 to 2022 at our institution. Software was developed to automate the extraction of all intraoperatively used personnel and material resources from the electronic medical record. Total costs were determined through a combination of direct observation, electronic medical record extraction, and interdepartmental collaboration (business operations, sterile processing, pharmacy, and plant operation departments). Multivariable linear regression analysis was performed to compare costs between TLIF modalities, accounting for patient-specific factors as well as number of levels fused, surgeon, and hospital site. RESULTS: The average total intraoperative cost per case for the RA-TLIF, ION-TLIF, and freehand TLIF cohorts was $24 838 ± $10 748, $15 991 ± $6254, and $14 498 ± $6580, respectively. Regression analysis revealed that RA-TLIF had significantly higher intraoperative cost compared with both ION-TLIF (ß-coefficient: $7383 ± $1575, P < .001) and freehand TLIF (ß-coefficient: $8182 ± $1523, P < .001). These cost differences were primarily driven by supply cost. However, there were no significant differences in intraoperative cost between ION-TLIF and freehand TLIF ( P = .32). CONCLUSION: We demonstrate a novel use of time-driven activity-based costing methodology to compare different modalities for executing the same type of lumbar fusion procedure. RA-TLIF entails significantly higher supply cost when compared with other modalities, which explains its association with higher total intraoperative cost. The use of ION, however, does not add extra expense compared with freehand TLIF when accounting for confounders. This might have implications as surgeons and hospitals move toward bundled payments.

D-Pinitol improves cognitive dysfunction and neuronal damage induced by isoproterenol via modulation of NF-κB/BDNF/GFAP signaling in Swiss albino mice.

Objectives: Neurological disorders are the world's most distressing problem. The adverse effects of current medications continue to compel scientists to seek safer, more effective, and economically affordable alternatives. In this vein, we explored the effect of D-Pinitol on isoproterenol-induced neurotoxicity in mice. Materials and Methods: Forty-two mice were randomly distributed into 7 groups each having 6 animals. Group I; received saline. Group II; received isoproterenol (ISO) 15 mg/kg/day, s.c. for 20 days. Group III, IV; received 50 and 100 mg/kg/day/oral of D-Pinitol, respectively along with ISO for 20 days. Group V; received D-Pinitol 100 mg/kg/day/oral for 20 days. Group VI; received propranolol 20 mg/kg/day/oral and ISO for 20 days. Group VII; received propranolol 20 mg/kg/day/oral for 20 days. On the 21st day after behavioral tests, blood was collected and mice were sacrificed for various biochemical, histopathological, and immunohistochemical analyses. Results: Chronic administration of isoproterenol caused neurotoxicity, cognitive dysfunction, and histopathological changes in the brain as evidenced by increase in GFAP, oxidative stress (via SOD, CAT, TBARS, and GSH), neuroinflammation (NF-kB, TNF-α, IL-6, and IL-10), and decrease in AchE and BDNF. Co-administration of D-Pinitol (100 mg/kg) significantly prevented these pathological alterations. The cognitive improvement was also observed through the forced swim test, elevated plus maze test, and rotarod test. Conclusion: Our findings on D-Pinitol thus clearly established its neuroprotective role in ISO-induced neurodegeneration in Swiss albino mice.

Does Body Mass Index Influence Intraoperative Costs and Operative Times for Anterior Cervical Discectomy and Fusion? A Time-Driven Activity-Based Costing Analysis.

OBJECTIVE: Spine surgeons are often unaware of drivers of cost variation for anterior cervical discectomy and fusion (ACDF). We used time-driven activity-based costing to assess the relationship between body mass index (BMI), total cost, and operating room (OR) times for ACDFs. METHODS: Total cost was divided into direct and indirect costs. Individual costs were obtained by direct observation, electronic medical records, and through querying multiple departments. Timestamps for all involved personnel and material resources were documented. Total intraoperative costs were estimated for all ACDFs from 2017 to 2022. All patients were categorized into distinct BMI-based cohorts. Linear regression models were performed to assess the relationship between BMI, total cost, and OR times. RESULTS: A total of 959 patients underwent ACDFs between 2017 and 2022. The average age and BMI were 58.1 ± 11.2 years and 30.2 ± 6.4 kg/m2, respectively. The average total intraoperative cost per case was $7120 ± $2963. Multivariable regression analysis revealed that BMI was not significantly associated with total cost (P = 0.36), supply cost (P = 0.39), or personnel cost (P = 0.20). Higher BMI was significantly associated with increased time spent in the OR (P = 0.018); however, it was not a significant factor for the duration of surgery itself (P = 0.755). Rather, higher BMI was significantly associated with nonoperative OR time (P < 0.001). CONCLUSIONS: Time-driven activity-based costing is a feasible and scalable methodology for understanding the true intraoperative costs of ACDF. Although higher BMI was not associated with increased total cost, it was associated with increased preparatory time in the OR.

Smartphone-based activity tracking for spine patients: Current technology and future opportunities.

Activity trackers and wearables allow accurate determination of physical activity, basic vital parameters, and tracking of complex medical conditions. This review attempts to provide a roadmap for the development of these applications, outlining the basic tools available, how they can be combined, and what currently exists in the marketplace for spine patients. Various types of sensors currently exist to measure distinct aspects of user movement. These include the accelerometer, gyroscope, magnetometer, barometer, global positioning system (GPS), Bluetooth and Wi-Fi, and microphone. Integration of data from these sensors allows detailed tracking of location and vectors of motion, resulting in accurate mobility assessments. These assessments can have great value for a variety of healthcare specialties, but perhaps none more so than spine surgery. Patient-reported outcomes (PROMs) are subject to bias and are difficult to track frequently - a problem that is ripe for disruption with the continued development of mobility technology. Currently, multiple mobile applications exist as an extension of clinical care. These include Manage My Surgery (MMS), SOVINITY-e-Healthcare Services, eHealth System, Beiwe Smartphone Application, QS Access, 6WT, and the TUG app. These applications utilize sensor data to assess patient activity at baseline and postoperatively. The results are evaluated in conjunction with PROMs. However, these applications have not yet exploited the full potential of available sensors. There is a need to develop smartphone applications that can accurately track the functional status and activity of spine patients, allowing a more quantitative assessment of outcomes, in contrast to legacy PROMs.

Primary Testicular Lymphoma Mimicking Germ-Cell Tumor: A Case Report.

There are 1% to 2% of lymphoma cases that include the testis as primary testicular non-Hodgkin lymphoma (NHL). In 35% of cases, it involves both testes and is usually seen as a painless testicular mass. Therefore, in most cases, the management option is radical orchiectomy. The overall prognosis in these cases is poor, as most cases are associated with systemic disease. We report a case of a 42-year-old male who presented with painless right scrotal swelling for three months. The only serologic marker of solid tumors that was elevated was ßHCG; others were unremarkable. Ultrasonography was initially ordered as well and showed a heterogeneous intra-testicular lesion of relatively low echogenicity. According to the given age, epidemiology, and clinical presentation, the suspicion of a germ cell tumor was highly likely. Therefore, a right radical inguinal orchiectomy was done, and the specimen was sent for histopathology, which came back as B-cell non-Hodgkin lymphoma. The clinical presentation and the overall picture of the investigations made in this case mimicked a germ cell tumor presentation.

A single-center, single-blinded, randomized, parallel-group, non-inferiority trial to compare the efficacy of a 22-gauge needle versus a 15 blade to perform an Achilles tendon tenotomy in 244 clubfeet-study protocol.

BACKGROUND: Achilles tendon tenotomy is an integral part of the Ponseti method, aimed at correcting residual equinus and lack of dorsiflexion after correction of the adductus deformity in clubfoot. Percutaneous tenotomy using a number 15 scalpel blade is considered the gold standard, resulting in excellent results with minimal complications. The use of a large-bore needle to perform Achilles tendon tenotomies has been described in literature, but a large-scale randomized controlled trial is currently lacking. In this trial, we aim to show the non-inferiority of the needle tenotomy technique compared to the gold standard blade tenotomy technique. METHODS: We will randomize 244 feet into group A: needle tenotomy or group B: blade tenotomy. Randomization will be done using a block randomization with random block sizes and applying a 1:1 allocation to achieve an intervention and control group of the exact same size. Children will be evaluated at 3 weeks and 3 months post-tenotomy for primary and secondary clinical outcomes. The primary clinical outcome will be the range of dorsiflexion obtained the secondary clinical outcomes will be frequency of minor and major complications and Pirani score. The non-inferiority margin was set at 4°, and thus, the null hypothesis of inferiority of the needle technique will be rejected if the mean difference between both techniques is less than 4°. The statistical analysis will use a multi-level mixed effects linear regression model for the primary outcomes and a multi-level mixed effects logistic regression model for the secondary clinical outcomes. The physician performing the evaluations post-tenotomy will be the only one blinded to group allocation. TRIAL REGISTRATION: This trial was registered prospectively with ClinicalTrials.gov registration number: NCT04897100 on 21 May 2021.

The platinum coordination complex inhibits cell invasion-migration and epithelial-to-mesenchymal transition by altering the TGF-ß-SMAD pathway in colorectal cancer.

Introduction: There is a steady increase in colorectal cancer (CRC) incidences worldwide; at diagnosis, about 20 percent of cases show metastases. The transforming growth factor-beta (TGF-ß) signaling pathway is one of the critical pathways that influence the expression of cadherins allowing the epithelial-to-mesenchymal transition (EMT), which is involved in the progression of the normal colorectal epithelium to adenoma and metastatic carcinoma. The current study aimed to investigate the impact of a novel coordination complex of platinum (salicylaldiminato) PT(II) complex with dimethyl propylene linkage (PT-complex) on TGF-ß and EMT markers involved in the invasion and migration of the human HT-29 and SW620 CRC cell lines. Methods: Functional study and wound healing assay showed PT-complex significantly reduced cell motility and the migration and invasion of CRC cell lines compared to the untreated control. Western blot performed in the presence and absence of TGF-ß demonstrated that PT-complex significantly regulated the TGF-ß-mediated altered expressions of EMT markers. Results and Discussion: PT-complex attenuated the migration and invasion by upregulating the protein expression of EMT-suppressing factor E-cadherin and suppressing EMT-inducing factors such as N-Cadherin and Vimentin. Moreover, PT-complex significantly suppressed the activation of SMAD3 in both CRC cell lines. Further, the microarray data analysis revealed differential expression of genes related to invasion and migration. In conclusion, besides displaying antiproliferative activity, the PT complex can decrease the metastasis of CRC cell lines by modulating TGF-ß-regulated EMT markers. These findings provide new insight into TGF-ß/SMAD signaling as the molecular mechanism involved in the antitumoral properties of novel PT-complex.

19†Unilateral lateral rectus resection as preferred procedure to treat patients with acquired distance esotropia.

To report the results of a series of patients with acquired distance esotropia (ET) who underwent lateral rectus resection.We retrospectively analysed data from 21 symptomatic patients with acquired esotropia who did not tolerate prisms. Twelve patients had myopic esotropia, 5 patients decompensated esophoria and 4 patients age-related distance esotropia. Patients were divided in two groups; myopic and non myopic. Two patients in each group had undergone surgery to medial recti muscles previously. Near and distance angles were measured over 2 visits. Data were analysed with t-test (paired and unpaired).Average age was 47 (myopes), 77 (distance ET) and 26 years (esophoria). Mean spherical equivalent was -4.00 DS (myopes) and + 1 SD (non myopes). Lateral rectus resection ranged between 6 and 8 mm with an average of 7 mm in the myopic group and between 4 and 8 mm with an average of 6 mm in the non-myopic group.The distance angle was reduced from 19 PD to 6 PD in myopes (mean difference 12 PD, p<0.0001) and from 19 PD to 8 PD in non myopes (mean difference 12 PD, p=0.0011). There was no difference in reduction of distance angle between myopes and non-myopes (p=0.771). All patients had complete resolution of diplopia after surgery without needing prisms. Near angle was also fully corrected in 19 patients. One patient with myopia and one patient with distance esotropia went on to have medial rectus recession.Unilateral lateral rectus resection is an effective procedure for acquired distance esotropia in myopic and non-myopic patients.

The impact of periodontal disease on the clinical outcomes of COVID-19: A systematic review and meta-analysis.

BACKGROUND: A possible relationship between periodontitis (PD) and COVID-19 and its adverse outcomes has been suggested. Hence, the present systematic review and meta-analysis aimed to investigate the available evidence regarding the potential association between periodontitis (PD) and COVID-19 and its adverse outcomes. MATERIALS AND METHODS: PubMed, Scopus, Web of Science, and Google Scholar were searched for relevant studies published up to April 15th, 2023. Studies that evaluated the association between PD and COVID-19 were included. Risk of bias was evaluated by two reviewers, and meta-analyses were performed using RevMan 5.3 software. RESULTS: A total of 22 studies involving 92,535 patients from USA, Europe, Asia, the Middle East and South America were included; of these, 12 were pooled into the meta-analysis. Most of the studies (19 studies) reported a significant association between PD and COVID-19. The pooled data found a significant association between PD and COVID-19 outcomes: more severe symptoms (OR = 6.95, P = 0.0008), ICU admissions (OR = 3.15, P = 0.0001), and mortality (OR = 1.92, P = 0.21). Additionally, compared to mild PD, severe PD was significantly associated with higher risks of severe COVID-19 outcomes: severe symptoms (P = 0.02); ICU admission (P = 0.0001); and higher mortality rates (P = 0.0001). The results also revealed 58% higher risk for COVID-19 infection in patients with PD (P = 0.00001). CONCLUSIONS: The present findings suggest a possible association between poor periodontal health and the risk of poor COVID-19 outcomes. However, owing to the observed methodological heterogeneity across the included studies, further prospective cohort studies with standardized methodologies are warranted to further unravel the potential association between periodontal disease and COVID-19 and its adverse outcomes.

Exploring the role of miR-200 family in regulating CX3CR1 and CXCR1 in lung adenocarcinoma tumor microenvironment: implications for therapeutic intervention.

Lung adenocarcinoma (LUAD) is the most common malignant subtype of lung cancer (LC). miR-200 family is one of the prime miR regulators of epithelial-mesenchymal transition (EMT) and worst overall survival (OS) in LC patients. The study aimed to identify and validate the key differentially expressed immune-related genes (DEIRGs) regulated by miR-200 family which may serve for therapeutic aspects in LUAD tumor microenvironment (TME) by affecting cancer progression, invasion, and metastasis. The study identified differentially expressed miRNAs (DEMs) in LUAD, consisting of hsa-miR-200a-3p and hsa-miR-141-5p, respectively. Two highest-degree subnetwork motifs identified from 3-node miRNA FFL were: (i) miR-200a-3p-CX3CR1-SPIB and (ii) miR-141-5p-CXCR1-TBX21. TIMER analysis showed that the expression levels of CX3CR1 and CXCR1 were significantly positively correlated with infiltrating levels of M0-M2 macrophages and natural killer T (NKT) cells. The OS of LUAD patients was significantly affected by lower expression levels of hsa-miR-200a-3p, CX3CR1 and SPIB. These DEIRGs were validated using the human protein atlas (HPA) web server. Further, we validated the regulatory role of hsa-miR-200a-3p in an in-vitro indirect co-culture model using conditioned media from M0, M1 and M2 polarized macrophages (THP-1) and LUAD cell lines (A549 and H1299 cells). The results pointed out the essential role of hsa-miR-200a-3p regulated CX3CL1 and CX3CR1 expression in progression of LC TME. Thus, the study augments a comprehensive understanding and new strategies for LUAD treatment where miR-200 family regulated immune-related genes, especially chemokine receptors, which regulate the metastasis and invasion of LUAD, leading to the worst associated OS.