Molecular glues and induced proximity: An evolution of tools and discovery.

Small molecule molecular glues can nucleate protein complexes and rewire interactomes. Molecular glues are widely used as probes for understanding functional proximity at a systems level, and the potential to instigate event-driven pharmacology has motivated their application as therapeutics. Despite advantages such as cell permeability and the potential for low off-target activity, glues are still rare when compared to canonical inhibitors in therapeutic development. Their often simple structure and specific ability to reshape protein-protein interactions pose several challenges for widespread, designer applications. Molecular glue discovery and design campaigns can find inspiration from the fields of synthetic biology and biophysics to mine chemical libraries for glue-like molecules.

Discovery of a Functional Covalent Ligand Targeting an Intrinsically Disordered Cysteine within MYC.

MYC is a major oncogenic transcriptional driver of most human cancers that has remained intractable to direct targeting because much of MYC is intrinsically disordered. Here, we have performed a cysteine-reactive covalent ligand screen to identify compounds that could disrupt the binding of MYC to its DNA consensus sequence in vitro and also impair MYC transcriptional activity in situ in cells. We have identified a covalent ligand, EN4, that targets cysteine 171 of MYC within a predicted intrinsically disordered region of the protein. We show that EN4 directly targets MYC in cells, reduces MYC and MAX thermal stability, inhibits MYC transcriptional activity, downregulates multiple MYC transcriptional targets, and impairs tumorigenesis. We also show initial structure-activity relationships of EN4 and identify compounds that show improved potency. Overall, we identify a unique ligandable site within an intrinsically disordered region of MYC that leads to inhibition of MYC transcriptional activity.

Comparison of the efficacy of metronidazole and metronidazole plus probiotics capsule in the treatment of bacterial vaginosis among non-pregnant patients seen at the outpatient department of a tertiary hospital: A single blind randomized controlled trial / Philippine Journal of Obstetrics and Gynecology

BACKGROUND: Bacterial vaginosis (BV) is the most prevalent cause of symptomatic vaginitis. In the Philippines, prevalence of BV is at 28.16%. The mainstay for the treatment of BV is Metronidazole. Although antibiotic therapy has been shown to eliminate BV associated organisms, there is extremely high recurrence rate.OBJECTIVE: To compare the efficacy of metronidazole and metronidazole plus lactobacilli tablet in the treatment of bacterial vaginosis among non-pregnant patients seen at the outpatient department of a tertiary medical center.METHODOLOGY: The population included non-pregnant women ages 15 t0 44 years old, with bacterial vaginosis diagnosed by Amsel's criteria and Nugent's scoring. The participants were randomly assigned to their treatment group, one is Metronidazole only and other received Metronidazole plus Lactobacillus tablet. All participants followed up on day 8,15,22 and 56 from initiation of treatment resolution or persistence of symptoms and collection of vaginal specimen for gram stain and inquire on adverse effects.RESULTS: On day 8 treatment, there were significantly more participant in the metronidazole plus probiotic arm with an estimated lactobacilli count of more than 30/hpf as comapred to metronidazole alone. On day 15 post treatment, there was no statistically significant difference with the estimated Gardnerella vaginalis count, lactobacilli count, presence or absence of malodorous vaginal discharge between the metronidazole plus probiotic and the metronidazole alone arm. With metronidazole plus probiotic group, the proportion of women with less than 30 per hpf Gardnella vaginalis count and absent foul smelling vaginal discharge were accounted among 100% of the participants from day 8 to 56 post treatment. The early reduction in the causative agent and symptoms can be attributed to an increase in the estimated lactobacilli count sustained until 56 days post treatment metronidazole plus probiotic. However, from day 15 to 22 and 56 post- treatment, the proportion of participants who had a nugent's score of less than 4 were greater for both the metronidazole plus probiotic (100%) and metronidazole alone (95%) arm, when compared to day 8 post-treatment. This finding for the metronidazole plus probiotic group is due to sustained reduction in the Gardnella vaginalis count and increase in lactobacilli counts. Potentially , the metronidazole plus probiotic treatment was found to be more favorable in sustaining the normal flora and probiotic can be used as an adjunct may enhance the efficacy of metronidazole in the treatment of BV.CONCLUSION: Metronidazole plus probiotic and metronidazole only treatment are comparable in treating bacterial vaginosis. In terms of restoring and maintaining the normal flora, metronidazole plus probiotic appears to be more significantly efficacious. Probiotic in the form of lactobacilli is a promising adjunct to enhance the efficacy of metronidazole in the treatment of bacterial vaginosis.

Metronidazole with Lactacyd vaginal gel in bacterial vaginosis.

AIM: To assess the efficacy and tolerability of lactic acid (Lactacyd vaginal gel; LVG) when given as an adjunct to metronidazole in the treatment of bacterial vaginosis (BV) among Filipino patients. METHODS: A multicenter, open-labeled, controlled, randomized, three-arm comparative study on 90 women aged 18 years or over with clinically and microbiologically proven BV. RESULTS: The lactobacilli colony count significantly increased over time in all three arms. At day 14, growth of lactobacilli was significantly higher among patients in the lactic acid gel and combination treatment arms. Significant reduction of malodorous vaginal discharge (whiff test) and lowest recurrence of BV were noted in the metronidazole plus lactic acid gel arm. Regarding disappearance of signs of BV, there was significant decrease in the pH level and frequency of clue cell positive patients across time but was not significantly different across treatment groups. Only one patient (3%, 1/60) among those who received lactic acid gel complained of increased curd-like discharge. Six patients (10%, 6/60) who received metronidazole complained of epigastric pain/discomfort, dizziness and dyspnea. CONCLUSIONS: Lactic acid gel (LVG) is safe and as efficacious as metronidazole in the treatment of BV. There is evidence that LVG when combined with metronidazole is superior to metronidazole alone in promoting lactobacilli colonization. LVG as an adjunct to metronidazole, having the least number of recurrent BV, appears to result in better long-term treatment effect on bacterial vaginosis.

Electron-beam CT as a diagnostic modality in pediatric nephrology and renal transplant surgery.

Electron-beam computed tomography is an imaging technology with a variety of medical applications, primarily in cardiology due to its sub-second acquisition time enabling visualization of a beating heart. Recently, this technique has also been introduced into other fields because of lower radiation exposure compared to traditional computed tomography, as well as the strengths of post-procedural three-dimensional visualization. This report evaluates electron-beam computed tomography as a diagnostic modality in pediatric nephrology patients. Seven patients reflecting typical clinical scenarios in pediatric nephrology were reviewed with regard to the value of electron-beam computed tomography and its contribution to the diagnostic workup. Electron-beam computed tomography is noninvasive and allows three-dimensional post-processing, enabling highly accurate images while requiring less radiation and acquisition time. It is very useful for clinical questions that require a detailed description of vascular and renal anatomy.

Three dimensional CT angiography for patients with congenital heart disease: scanning protocol for pediatric patients.

The objective of our study was to determine the contrast attenuation level that yields high quality cardiac three-dimensional (3-D) images and to predict the contrast injection rate (IR), from body weight, to reach this attenuation level. Enhanced electron beam computerized tomography (EBCT) with 3-D reconstruction is useful in delineating cardiac anatomy in complex congenital heart disease (CHD). The current experience of using electron beam angiography (EBA) in pediatric CHD is limited. Well-defined contrast injection protocols, specifically the contrast IR, have not been standardized when compared to those for adults. Establishing the contrast IR is essential in obtaining high quality 3-D images. We retrospectively analyzed the studies of 115 pediatric patients with CHD. EBA images were divided into group 1 with good quality 3-D images and group 2 with poor quality. The mean of measured enhancement level, expressed in Hounsfield units (HU), and contrast IR were analyzed in both groups. Spearman correlation was used to examine the relationship between weight and IR. The IR was predicted from weight using simple linear regression analysis. The mean level of enhancement was 344 +/- 91 and 174 +/- 31 HU for group 1 and group 2, respectively. Group 1 consisted of 103 patients (90%) and the IR strongly correlated with weight (rho = 0.861, P < 0.01). The IR was estimated from the linear regression equation IR = 0.59 + 0.056 x weight. Necessary contrast enhancement level for quality 3-D reconstruction should be greater than 250 HU, and the IR can be estimated from patient's weight.

Universal precautions guideline: self-reported compliance by gastroenterologists and gastrointestinal endoscopy nurses--a decade's lack of progress.

OBJECTIVES: The aims of this study were to assess and compare the Universal Precaution (UP) practices of gastroenterologists (GE) and GI endoscopy nurses (GIEN). METHODS: We mailed a 23-item questionnaire to 250 GE and GIEN selected, respectively, from the American Board of Internal Medicine online directory and the Society of Gastroenterology Nurses and Associates membership directory. RESULTS: A total of 77 (31%) GE and 157 (60%) GIEN responded. In all, 32% of GE and 50% of GIEN washed their hands before and after handling every patient (p<0.01), and 5% of GE and 30% of GIEN wore gloves during all patient contacts (p<0.01). Fewer GE than GIEN used face shields for all procedures (14% vs 21%; p=0.02). Protective gowns were worn during all procedures by 29% of GE and 46% of GIEN (p<0.01). More GE than GIEN either did not recap used needles or used the one-handed "scoop" technique (85% vs 77%; p=0.02). When asked to give an overall assessment, 46% of GE and 60% of GIEN reported that they always complied with UP (p=0.06). Profession, age, gender, hours of daily patient contact, and adequacy of staffing did not affect compliance. CONCLUSIONS: GIEN adhered to UP recommendations better than GE regarding most items queried except in the handling of used needles. Nonetheless, for both groups, compliance with proper hand washing and use of gloves, face shields, and gowns was very poor, and handling of used needles was satisfactory.