While inhibitors of BCL-2 family proteins (BH3 mimetics) have shown promise as anti-cancer agents, the various dependencies or co-dependencies of diverse cancers on BCL-2 genes remain poorly ...understood. Here we develop a drug screening approach to define the sensitivity of cancer cells from ten tissue types to all possible combinations of selective BCL-2, BCL-X
, and MCL-1 inhibitors and discover that most cell lines depend on at least one combination for survival. We demonstrate that expression levels of BCL-2 genes predict single mimetic sensitivity, whereas EMT status predicts synergistic dependence on BCL-X
+MCL-1. Lastly, we use a CRISPR/Cas9 screen to discover that BFL-1 and BCL-w promote resistance to all tested combinations of BCL-2, BCL-X
, and MCL-1 inhibitors. Together, these results provide a roadmap for rationally targeting BCL-2 family dependencies in diverse human cancers and motivate the development of selective BFL-1 and BCL-w inhibitors to overcome intrinsic resistance to BH3 mimetics.
Altered mitochondrial dynamics can broadly impact tumor cell physiology. Using genetic and pharmacological profiling of cancer cell lines and human tumors, we here establish that perturbations to the ...mitochondrial dynamics network also result in specific therapeutic vulnerabilities. In particular, through distinct mechanisms, tumors with increased mitochondrial fragmentation or connectivity are hypersensitive to SMAC mimetics, a class of compounds that induce apoptosis through inhibition of IAPs and for which robust sensitivity biomarkers remain to be identified. Further, because driver oncogenes exert dominant control over mitochondrial dynamics, oncogene-targeted therapies can be used to sensitize tumors to SMAC mimetics via their effects on fission/fusion dynamics. Collectively, these data demonstrate that perturbations to the mitochondrial dynamics network induce targetable vulnerabilities across diverse human tumors and, more broadly, suggest that the altered structures, activities, and trafficking of cellular organelles may facilitate additional cancer therapeutic opportunities.
Abstract: This study aimed to examine the effect of using oleogel as a frying medium on the quality of coated and deep-fried chicken products. Sunflower oil-based oleogels prepared with 0.5%, 1%,1.5% ...and 2% carnauba wax were produced for deep frying of coated chicken products and were compared to sunflower and commercial frying oil based on palm oil. The increased carnauba wax concentration in the oleogel decreased the pH, oil, oil absorbance and TBARS value of coated chicken (p<0.05). Samples deep-fried with oleogels containing 1.5% and 2% carnauba wax had the lowest pH values. In addition, since the oil absorption during deep-frying was significantly reduced in these groups (1.5 and 2%), the fat contents of coated products were also lower (p<0.05). The use of oleogel as a frying medium did not cause a significant change in the color values of the coated chicken products. However, the increased carnauba wax concentration in the oleogel increased the hardness of coated chicken (p<0.05). As a result, sunflower oil-based oleogels with a carnauba wax content of 1.5% and higher which is healthier in terms of saturated fat content can be used as frying media and can be improved the quality of coated and deep-fried chicken products.
Objective
To evaluate stability outcomes and failure rates associated with four types of lingual retainers: (1) dead‐soft wire, (2) multistrand stainless steel (SS) wire, (3) CAD/CAM nitinol, and (4) ...connected bonding pads (CBPs) after 3 years of retention.
Methods
This study enrolled 96 patients (66 females, 30 males) with a median age of 19 years with four types of lingual retainers: (1) 0.016 × 0.022‐inch dead‐soft wire, (2) 0.0215‐inch five‐strand SS wire, (3) 0.014 × 0.014‐inch CAD/CAM nitinol wire, and (4) CBPs. The irregularity index, intercanine distances, and arch lengths were obtained and used to evaluate mandibular stability. Failure rates were also assessed during this study. Data were statistically analysed.
Results
Irregularity increased, whereas intercanine width and arch length decreased after 3 years of retention. The greatest irregularity was associated with the CBPs and the least with the CAD/CAM retainers. Changes in stability measurements were significantly higher in the dead‐soft wire and CBPs than those in the CAD/CAM nitinol and multistrand SS wires. Parallel to these changes, the frequency of failure yielded similar results with the same significance between the groups. The failure rate of CBPs, in contrast to the CAD/CAM nitinol and multistrand SS wires, was significantly higher in the right quadrant (P < .05).
Conclusion
After taking the 3‐year results into consideration, CAD/CAM nitinol and multistrand SS wires were found to be more successful than the others in maintaining mandibular stability. The most failures were observed with CBPs after 3 years of retention.
Introduction and Hypothesis
We aimed to evaluate the outcomes, complication rates, and complication types of different labiaplasty techniques.
Methods
In this cross-sectional retrospective study, a ...total of 2,594 patients who underwent surgery owing to hypertrophy or asymmetry of the labium minus were retrospectively analyzed. Data were collected by individual interviews with 43 experts from different centers. The patients were between 18 and 50 years of age. During the interview information about the presence and nature of complications, and about concomitant or revision surgeries, were gathered. The surgeons who performed these surgeries were also questioned about their training and surgical experience.
Results
The most frequently observed complication was complete dehiscence, accounting for 29% of all complications. Complete dehiscence was most commonly seen after wedge resection (16 cases). The second most common complication was labium majus hematoma, accounting for 12.5% of all cases. Among the labiaplasty techniques, wedge resection had the highest complication rate at 3% (26 cases out of 753 patients). This was followed by composite labiaplasty at 1.2% (5 cases out of 395 patients), Z-plasty at 0.8% (1 case out of 123 patients), and trimming labiaplasty at 0.5% (7 cases out of 1,323 patients).
Conclusion
Considering the heterogeneity and low quality of the existing studies on this subject, this study provides valuable information for surgeons practicing in this field. However, further research is clearly warranted as female genital aesthetic procedures are being performed with a steadily increasing trend.
Objective: To evaluate the role of hand-wrist radiographs (HWRs) in the assessment of growth and development based on the cervical vertebral maturation (CVM) method and to determine whether clinical ...experience levels would affect the decision-making process. Materials and Methods: The lateral cephalometric radiographs and HWRs of 48 patients aged 11 to 16 years were assessed in this study. The clinicians first determined the growth stage by the CVM method based on lateral cephalometric images (T1). Then, the clinicians filled out the same questionnaire with HWRs on each question (T2). Subsequently, the clinicians were divided into groups according to their experience levels. Intraclass correlation coefficients were calculated to evaluate intraobserver agreements. The data were analyzed with chi-square or Fisher-Freeman-Halton Exact tests for intergroup comparisons. Results: For all evaluators, the percentage of agreement changed minimally after T2. The most experienced clinicians demonstrated the most consistent decisions for overall CVM stages at both evaluations. Concerning each stage, the percentages of changed decisions showed no significant differences between the groups except for stages CS4 and CS5. There were significant differences between the rates of agreement for CS3 in each group from T1 to T2 (p<0.05). Conclusion: The level of orthodontic experience affects the decision-making process. The presence of HWRs provided no advantage in the assessment of CVM.
The objective was to evaluate the influence of residual bone height (RBH) and implant macro-design on the primary stability (PS) of implants using a simultaneous sinus floor elevation (SFE) and ...implant insertion model. Fresh bovine rib samples that resembled type-IV density that were confirmed by computerized tomography were prepared to represent 4 groups of varying RBHs (3, 6, 9, 15 mm). To simulate simultaneous implant insertion with SFE, 120 implants in different macro-designs (group R: NobelReplace; group P: NobelParallel; group A: NobelActive, Nobel Biocare, Gothenburg, Sweden) were randomly inserted at RBHs of 3, 6, 9, and 15 mm in each rib. The implant stability quotient (ISQ) was measured immediately after implant insertion. RBH and implant macro-design have an impact on ISQ values (P < .001). ISQ values were the highest with RBH of 15 mm, followed by RBHs of 9, 6, and 3 mm. (P < .001). There was no statistically significant difference between different implant macro-designs at RBHs of 3 and 15 mm regarding ISQ values (P = .111, P = .551). ISQ values of group P were higher than those of group R and group A at an RBH of 6 mm (P = .049, P = .029). ISQ values were also higher in group P compared to group A at an RBH of 9 mm (P = .006). A higher PS may be expected in sites with higher RBH, regardless of the macro-design. In addition, cylindric implant design may enhance the PS at RBHs of 6 and 9 mm in simultaneous implant insertion with SFE.
Background: Ovarian hyperstimulation syndrome (OHSS) is characterized by collection of fluid in third spaces in in vitro fertilization (IVF) cycles and can result in the cancellation of the cycle and ...be fatal in 3 women out of 100,000. The aim of this study is to compare the admission of human chorionic gonadotropin (hCG) subcutaneously versus intracavitary during ovum pick-up (OPU) in agonist induced ovulation in IVF cycles in terms of pregnancy outcomes. Methods: This study was carried out in Kocaeli University Faculty of Medicine, Department of Obstetrics and Gynecology Assisted Reproductive Techniques Clinic as a retrospective study. 157 patients who underwent IVF treatment between January 2018 and February 2020, with ≥25 follicles detected in ultrasound and 1 mg of triptorelin acetate was administered for ovulation trigger, and 36 hours later of whom ≤20 oocytes were obtained in OPU were enrolled in this study. 109 patients who were administered 1500 IU of hCG subcutaneously belonged to Group 1, and 1500 IU hCG was administered intracavitary to 48 patients as Group 2. Results: Infertility causes, and characteristics of both groups were similar. Number of retrieved oocytes, Metaphase 2 (MII) oocytes and fertilization rates were similar in both groups. Implantation rate per embryo transferred was higher in the intracavitary group (p = 0.01). There was no significant difference for pregnancy rate, clinical pregnancy rate, ongoing pregnancy rate, livebirth rate and OHSS frequency between both groups. Twin pregnancy rate was significantly higher in the intracavitary group. Conclusions: Administration of 1500 IU hCG intracavitary at the time of OPU is associated with improved implantation rates when compared to subcutaneous hCG administration without a significant raise in OHSS occurrence. Prospective, randomized studies with bigger patient cohort are needed.
This study aimed to evaluate the effects of partially N-acetylated chitosans with a degree of acetylation (DA) of 10% on in vitro propagation of an ornamental plant, Ipomoea purpurea, by emphasizing ...the importance of the degree of polymerization (DP) on in vitro plant development. The effects of either a chitosan oligomer mixture with a DP between 2 and 15 (5.0, 10.0, and 20.0 mg L−1) or chitosan polymer with a DP of 70 were compared with commonly used cytokinins 6-benzylaminopurine (BAP) and kinetin (KIN) at 0.5, 1.0, 2.0, and 4.0 mg L−1 and auxins indole-3-acetic acid (IAA) and indole-3-butyric acid (IBA) at 0.25, 0.5, 1.0, and 2.0 mg L−1. The nodal explants used in this study were taken from donor plants obtained by germination of the seeds. The results indicated that all chitosan treatments had positive effects on the shoot induction, but only the oligomer mixture at 5 mg L−1 gave the best results for mean shoot number, shoot length, and leaf number, compared to the other treatments and control. Also, all chitosan treatments increased mean number of roots and triggered adventitious root induction. However, root elongation was decreased in the presence of chitosan in the medium. The root elongation-inhibitory effects of chitosan become clearer in the presence of oligomer mixture. In general, chitosan had similar effects with tested cytokinins rather than auxins. The results of this study suggested that the application of chitosan oligomers—rather than polymers—can be an ecofriendly and effective alternative to synthetic cytokinins in horticulture.
Combinatorial inhibition of effector and feedback pathways is a promising treatment strategy for KRAS mutant cancers. However, the particular pathways that should be targeted to optimize therapeutic ...responses are unclear. Using CRISPR/Cas9, we systematically mapped the pathways whose inhibition cooperates with drugs targeting the KRAS effectors MEK, ERK, and PI3K. By performing 70 screens in models of KRAS mutant colorectal, lung, ovarian, and pancreas cancers, we uncovered universal and tissue-specific sensitizing combinations involving inhibitors of cell cycle, metabolism, growth signaling, chromatin regulation, and transcription. Furthermore, these screens revealed secondary genetic modifiers of sensitivity, yielding a SRC inhibitor-based combination therapy for KRAS/PIK3CA double-mutant colorectal cancers (CRCs) with clinical potential. Surprisingly, acquired resistance to combinations of growth signaling pathway inhibitors develops rapidly following treatment, but by targeting signaling feedback or apoptotic priming, it is possible to construct three-drug combinations that greatly delay its emergence.
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•Scalable CRISPR screening identifies combination therapies for KRAS-driven cancers•Identification of tissue-specific and secondary modifiers of sensitivity•Clinical promise of combined MAPK and SRC inhibition in KRAS/PIK3CA mutant CRC•Key strategies to control the rapid evolution of resistance to two-body combinations
Anderson et al. develop a screening approach to rapidly uncover potent and durable combination therapies in KRAS-driven cancers. This scalable approach can be applied to diverse cancer types for the discovery of potent treatment strategies. Furthermore, they describe rational methods to engineer higher-order therapies to control tumor evolution.
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