Unveiling the mechanisms and challenges of cancer drug resistance.

Cancer treatment faces many hurdles and resistance is one among them. Anti-cancer treatment strategies are evolving due to innate and acquired resistance capacity, governed by genetic, epigenetic, proteomic, metabolic, or microenvironmental cues that ultimately enable selected cancer cells to survive and progress under unfavorable conditions. Although the mechanism of drug resistance is being widely studied to generate new target-based drugs with better potency than existing ones. However, due to the broader flexibility in acquired drug resistance, advanced therapeutic options with better efficacy need to be explored. Combination therapy is an alternative with a better success rate though the risk of amplified side effects is commonplace. Moreover, recent groundbreaking precision immune therapy is one of the ways to overcome drug resistance and has revolutionized anticancer therapy to a greater extent with the only limitation of being individual-specific and needs further attention. This review will focus on the challenges and strategies opted by cancer cells to withstand the current therapies at the molecular level and also highlights the emerging therapeutic options -like immunological, and stem cell-based options that may prove to have better potential to challenge the existing problem of therapy resistance. Video Abstract.

Assessment of extremely premature lambs supported by the Extrauterine Environment for Neonatal Development (EXTEND).

BACKGROUND: Our team has previously reported physiologic support by the EXTra-uterine Environment for Neonatal Development (EXTEND) of 105 to 117 days gestational age (GA) lambs for up to 28 days with normal organ maturation. However, the fetal lamb brain matures more rapidly, requiring the study of 90-105 day GA fetal lambs to assess more neurodevelopmentally equivalent lambs to the 23-25 week GA extreme premature infant. METHODS: Extremely preterm lambs (90-95 days of GA) were delivered by C-section and supported by EXTEND. Estimated circuit flows were maintained at around 325 ml/kg/min. After support on EXTEND, MRI and histopathologic analysis were performed and compared to 105-112 days GA control lambs. RESULTS: The extremely preterm group includes 10 animals with a mean GA of 91.6 days, a mean weight at cannulation of 0.98 kg and a mean length of stay on EXTEND of 13.5 days (10-21 days). Hemodynamics and oxygenation showed stable parameters. Animals showed growth and physiologic cardiac function. MRI volumetric and diffusion analysis was comparable to controls. Histologic brain analysis revealed no difference between study groups. CONCLUSION: EXTEND appears to support brain and cardiac development in an earlier gestation, less mature, lamb model. IMPACT: Prolonged (up to 21 days) physiological support of extremely preterm lambs of closer neurodevelopmental equivalence to the 24-28 gestational week human was achieved using the EXTEND system. EXTEND treatment supported brain growth and development in extremely preterm fetal lambs and was not associated with intraventricular hemorrhage or white matter injury. Daily echocardiography demonstrated physiologic heart function, absence of cardiac afterload, and normal developmental increase in cardiac chamber dimensions. This study demonstrates hemodynamic and metabolic support by the EXTEND system in the extremely preterm ovine model.

Investigating the characteristics of biomass wastes via particle feeder in downdraft gasifier.

Particle feeding plays a crucial role in the gasifier due to its effects on the efficiency and performance metrics of the thermochemical process. Investigating particle size distribution's impact on downdraft gasification reactor performance, this study delves into the significance of feedstock characteristics (moisture, volatile matter, fixed carbon, and ash contents) during the particle feeding stage. Various biomass wastes (date palm waste, olive pomace and sewage sludge) at diverse compositions and sizes are subjected to empirical determination of mass flow rates (MFR), power ratings, and storage times for each feedstock. The preheating process in the gasifier is considered, employing both an approximation and analytical solution. In addition, the influence of the equivalence ratio (ER) on the syngas yield is analyzed. The collected data reveals that for average particle size of 200 µm, the highest MFR (in g/min) are 0.518 ± 0.033, 7.691 ± 0.415, and 16.111 ± 1.050, for palm wood biomass, olive pomace and sewage sludge, respectively. Smaller particles (80 µm) led to extended storage times. Moreover, the lumped capacitance approximation method consistently underestimates preheating time, with a percentage error of 6.26%-17.08%. Response surface methodology (RSM) optimization analysis provides optimal gasification conditions for palm wood biomass, olive pomace, and sewage sludge with maximum cold gas efficiencies (CGEs) of 58.01%, 63.29%, and 52.27%. The peak conversion was attained at gasification temperatures of 1089.83 °C, 1151.93 °C, and 1102.91 °C for palm wood biomass, olive pomace, and sewage sludge, respectively. In addition, gasification equilibrium model determined optimal gasification temperatures as 1150 °C for palm biomass, 1200 °C for olive pomace, and 1150 °C for sewage sludge with respective syngas efficiencies of 59.62%, 64.13%, and 53.66%. Consequently, the examination of the dosing procedure, preheating dynamics, particle dimensions, ER, storage time, and their combined impacts offer practical insights to effectively control downdraft gasifiers in handling a variety of feedstocks.

Psoralen Isolated from the Roots of Dorstenia psilurus Welw. Modulate Th1/Th2 Cytokines and Inflammatory Enzymes in LPS-Stimulated RAW 264.7 Macrophages.

Dorstenia psilurus is a widely used plant spice in traditional African medicine to treat pain-related conditions. However, the anti-inflammatory mechanisms underlying this activity and the main active ingredients of D. psilurus have not yet been fully characterized. This study aimed to isolate and identify the main active anti-inflammatory constituents of the D. psilurus extract and to investigate the underlying anti-inflammatory mechanisms in murine macrophages. Chromatographic techniques and spectroscopic data were used for compound isolation and structure elucidation. The Griess reagent method and the ferrous oxidation-xylenol orange assay were used to evaluate the inhibition of NO production and 15-lipoxygenase activity, respectively. Cyclooxygenase activity was assessed using the fluorometric COX activity assay kit, and Th1/Th2 cytokine measurement was performed using a flow cytometer. The results indicated that the extract and fractions of D. psilurus inhibit NO production and proliferation of RAW 264.7 macrophage cells. Bioguided fractionation led to the identification of psoralen, a furocoumarin, as the main bioactive anti-inflammatory compound. Psoralen inhibited NO production and 15-lipoxygenase activity and reduced pro-inflammatory Th1 cytokines (IFN-γ, TNF-α, and IL-2) while increasing the secretion of anti-inflammatory cytokines (IL-4, IL-6, and IL-10) in activated RAW 264.7 macrophage cells. The encouraging results obtained in this study suggest that psoralen-based multiple modulation strategies could be a useful approach to address the treatment of inflammatory diseases.

Comparison between high transverse and low transverse Pfannenstiel skin incisions during cesarean delivery for morbidly obese patients.

OBJECTIVE: This study aimed to evaluate if placement of transverse cesarean skin incision above or below the overhanging pannus is associated with wound morbidity in morbidly obese patients. STUDY DESIGN: We identified a cohort of patients with body mass index (BMI) ≥40 kg/m2 undergoing cesarean delivery at a single center from 2017-2020 with complete postpartum records. Data was abstracted after institutional review board exemption, and patients were grouped by low transverse or high transverse skin incision. The primary outcome was a composite of wound infection, fascial dehiscence, incisional hernia, therapeutic wound vacuum, and reoperation. Secondary outcomes included the individual components of the composite, blood transfusion, operative time, and immediate neonatal outcome. T test and χ2 were used for continuous and categorical comparisons. Logistic regression was used to compute adjusted odds ratios for categorical outcomes and linear regression to compare operative times adjusting for factors associated with wound complications and surgical duration respectively. RESULTS: 328 patients met inclusion criteria: 65 with high transverse (infraumbilical and supraumbilical) and 263 with low transverse (Pfannenstiel) incision. 11% of patients had wound morbidity; high transverse incision was associated with 3.64-fold increased odds of composite wound morbidity (23.1% vs 8%, aOR 3.64, 95% CI 1.52-8.70) and 5.73-fold increased odds of wound infection (13.8% vs. 4.9%, aOR 5.73, 95% CI 1.83-17.96). Time from skin incision to delivery was 1.87 min longer (11.09 vs 14.98 min, ß = 1.87, 95% CI 0.17-4.61). There was no significant difference in neonatal outcomes, non-low transverse hysterotomy, or total operative time. CONCLUSION: High transverse skin incision for cesarean delivery was strongly associated with increased wound morbidity in morbidly obese patients.

Outcomes after cesarean delivery were assessed for 328 patients with morbid obesity.High transverse skin incision for cesarean delivery was associated with increased wound morbidity and wound infection.Prospective studies will be needed to determine if skin incision placement causes wound morbidity.

Biopolymeric Innovations in Ophthalmic Surgery: Enhancing Devices and Drug Delivery Systems.

The interface between material science and ophthalmic medicine is witnessing significant advances with the introduction of biopolymers in medical device fabrication. This review discusses the impact of biopolymers on the development of ophthalmic devices, such as intraocular lenses, stents, and various prosthetics. Biopolymers are emerging as superior alternatives due to their biocompatibility, mechanical robustness, and biodegradability, presenting an advance over traditional materials with respect to patient comfort and environmental considerations. We explore the spectrum of biopolymers used in ophthalmic devices and evaluate their physical properties, compatibility with biological tissues, and clinical performances. Specific applications in oculoplastic and orbital surgeries, hydrogel applications in ocular therapeutics, and polymeric drug delivery systems for a range of ophthalmic conditions were reviewed. We also anticipate future directions and identify challenges in the field, advocating for a collaborative approach between material science and ophthalmic practice to foster innovative, patient-focused treatments. This synthesis aims to reinforce the potential of biopolymers to improve ophthalmic device technology and enhance clinical outcomes.

Burns in South Asia: Outcomes from South Asian Burn Registry (SABR).

BACKGROUND: South Asian region contributes 59 % to the global mortality due to burns. However, we find a paucity of literature on the outcomes of burns from low- and middle-income countries (LMICs). South Asian Burn Registry (SABR) is a facility-based burns registry that collected data on in-patient burn care. This study assesses factors associated with mortality, length of hospital stay at the burns center, and functional status of burn patients. METHODS: Prospective data was collected from two specialized public sector burn centers between September 2014 - January 2015 from Bangladesh and Pakistan. Multivariable logistic, linear, and ordinal logistic regression was conducted to assess factors associated with inpatient-mortality, length of hospital stay, and functional status at discharge, respectively. RESULTS: Data on 883 patients was analyzed. Increased association with mortality was observed with administration of blood product (OR:3, 95 % CI:1.18-7.58) and nutritional support (OR:4.32, 95 % CI:1.55-12.02). Conversely, antibiotic regimens greater than 8 days was associated with decreased mortality (OR:0.1, 95 % CI:0.03-0.41). Associated increase in length of hospital stay was observed in patients with trauma associated with their burn injury, history of seizures (CE:47.93, 95 % CI 12.05-83.80), blood product (CE:22.09, 95 % CI:0.83-43.35) and oxygen administration (CE:23.7, 95 % CI:7.34-40.06). Patients who developed sepsis (OR:6.89, 95 % CI:1.92-24.73) and received blood products during hospitalization (OR:2.55, 95 % CI:1.38- 4.73) were more likely to have poor functional status at discharge. CONCLUSION: This study identified multiple factors associated with worse clinical outcomes for burn patients in South Asia. Understanding these parameters can guide targeted efforts to improve the process and quality of burn care in LMICs.

Somatostatin Receptor Imaging with [18F]FET-ßAG-TOCA PET/CT and [68Ga]Ga-DOTA-Peptide PET/CT in Patients with Neuroendocrine Tumors: A Prospective, Phase 2 Comparative Study.

There is a clinical need for 18F-labeled somatostatin analogs for the imaging of neuroendocrine tumors (NET), given the limitations of using [68Ga]Ga-DOTA-peptides, particularly with regard to widespread accessibility. We have shown that [18F]fluoroethyl-triazole-[Tyr3]-octreotate ([18F]FET-ßAG-TOCA) has favorable dosimetry and biodistribution. As a step toward clinical implementation, we conducted a prospective, noninferiority study of [18F]FET-ßAG-TOCA PET/CT compared with [68Ga]Ga-DOTA- peptide PET/CT in patients with NET. Methods: Forty-five patients with histologically confirmed NET, grades 1 and 2, underwent PET/CT imaging with both [18F]FET-ßAG-TOCA and [68Ga]Ga-peptide performed within a 6-mo window (median, 77 d; range, 6-180 d). Whole-body PET/CT was conducted 50 min after injection of 165 MBq of [18F]FET-ßAG-TOCA. Tracer uptake was evaluated by comparing SUVmax and tumor-to-background ratios at both lesion and regional levels by 2 unblinded, experienced readers. A randomized, blinded reading of both scans was also then undertaken by 3 experienced readers, and consensus was assessed at a regional level. The ability of both tracers to visualize liver metastases was also assessed. Results: A total of 285 lesions were detected on both imaging modalities. An additional 13 tumor deposits were seen in 8 patients on [18F]FET-ßAG-TOCA PET/CT, and [68Ga]Ga-DOTA-peptide PET/CT detected an additional 7 lesions in 5 patients. Excellent correlation in SUVmax was observed between both tracers (r = 0.91; P < 0.001). No difference was observed between median SUVmax across regions, except in the liver, where the median tumor-to-background ratio of [18F]FET-ßAG-TOCA was significantly lower than that of [68Ga]Ga-DOTA-peptide (2.5 ± 1.9 vs. 3.5 ± 2.3; P < 0.001). Conclusion: [18F]FET-ßAG-TOCA was not inferior to [68Ga]Ga-DOTA-peptide in visualizing NET and may be considered in routine clinical practice given the longer half-life and availability of the cyclotron-produced fluorine radioisotope.

Comparing students' performance in self-directed and directed self-learning in College of Medicine, University of Bisha.

Background: Student-centered learning strategy increases the likelihood of graduation of competent, self-dependent, and problem-solving physicians. The University of Bisha, College of Medicine (UBCOM) adopted self-directed learning (SDL) represented by problem-based learning (PBL), and directed self-learning (DSL) represented by team-based learning (TBL). Aim: To compare the students' performance in SDL and DSL among UBCOM students. Methodology: A total of 502 multiple choice questions (MCQs) from the mid-course and final exams were collected by the relevant subject experts from nine courses during the period from September 2020 till June 2023 that adopted PBL and TBL; 247 MCQs related to PBL and 255 related to TBL. Psychometric analysis was used to determine difficult, easy, and optimum questions (≤25%, ≥90%, and 26-89%, respectively). Point biserial as <0.19, 0.20-0.29, 0.30-0.39, and >0.40 which indicate poor, marginal, good, and excellent point biserial, respectively. Finally, the number of functional distractors was attempted by >5% of the candidates. Results: No significant differences were noted for the students' performance in MCQs related to PBL (representing self-directed, small group learning tool), and TBL (representing directed-self, large group learning tool) regarding difficulty index (DI), point biserial, and distractors functionality. Conclusion: It has been observed that there is no difference in students' performance whether PBL or TBL is used for learning Basic Medical Science courses. Small group learning such as PBL needs more resources in comparison to large group learning as in TBL, therefore any institute can decide on the adopted learning strategy depending on its resources and the number of students.