Development of potent and selective ULK1/2 inhibitors based on 7-azaindole scaffold with favorable in vivo properties.

The UNC-51-like kinase-1 (ULK1) is one of the central upstream regulators of the autophagy pathway, represents a key target for the development of molecular probes to abrogate autophagy and explore potential therapeutic avenues. Here we report the discovery, structure-activity and structure-property relationships of selective, potent, and cell-active ULK1/2 inhibitors based on a 7-azaindole scaffold. Using structure-based drug design, we have developed a series of analogs with excellent binding affinity and biochemical activity against ULK1/2 (IC50 < 25 nM). The validation of cellular target engagement for these compounds was achieved through the employment of the ULK1 NanoBRET intracellular kinase assay. Notably, we have successfully solved the crystal structure of the lead compound, MR-2088, bound to the active site of ULK1. Moreover, the combination treatment of MR-2088 with known KRAS→RAF→MEK→ERK pathway inhibitors, such as trametinib, showed promising synergistic effect in vitro using H2030 (KRASG12C) cell lines. Lastly, our findings underscore MR-2088's potential to inhibit starvation/stimuli-induced autophagic flux, coupled with its suitability for in vivo studies based on its pharmacokinetic properties.

Feasibility and Safety of 5G-Based Telerobotic Abdominal Ultrasonography.

OBJECTIVE: Telemedicine can offer services to remote patients regardless of the distance. Fifth-generation (5G) mobile networks may make telemedicine practical because of their low latency. This study aimed to evaluate the feasibility and safety of a novel 5G robot-assisted remote abdominal ultrasound (AUS) telemedicine technology in clinical applications in distant locations. METHODS: We performed 5G-based telerobotic AUS in patients who were located more than 100 km away from the physicians. RESULTS: The telerobotic AUS had a longer examination time than the conditional bedside AUS; however, the complete examination rate was not inferior. None of the volunteers experienced discomfort during the examination and the examination time was acceptable for all. CONCLUSION: Our findings confirm the feasibility and safety of 5G-based telerobotic AUS in clinical practice.

Chemical Proteomics with Novel Fully Functionalized Fragments and Stringent Target Prioritization Identifies the Glutathione-Dependent Isomerase GSTZ1 as a Lung Cancer Target.

Photoreactive fragment-like probes have been applied to discover target proteins that constitute novel cellular vulnerabilities and to identify viable chemical hits for drug discovery. Through forming covalent bonds, functionalized probes can achieve stronger target engagement and require less effort for on-target mechanism validation. However, the design of probe libraries, which directly affects the biological target space that is interrogated, and effective target prioritization remain critical challenges of such a chemical proteomic platform. In this study, we designed and synthesized a diverse panel of 20 fragment-based probes containing natural product-based privileged structural motifs for small-molecule lead discovery. These probes were fully functionalized with orthogonal diazirine and alkyne moieties and used for protein crosslinking in live lung cancer cells, target enrichment via "click chemistry," and subsequent target identification through label-free quantitative liquid chromatography-tandem mass spectrometry analysis. Pair-wise comparison with a blunted negative control probe and stringent prioritization via individual cross-comparisons against the entire panel identified glutathione S-transferase zeta 1 (GSTZ1) as a specific and unique target candidate. DepMap database query, RNA interference-based gene silencing, and proteome-wide tyrosine reactivity profiling suggested that GSTZ1 cooperated with different oncogenic alterations by supporting survival signaling in refractory non-small cell lung cancer cells. This finding may form the basis for developing novel GSTZ1 inhibitors to improve the therapeutic efficacy of oncogene-directed targeted drugs. In summary, we designed a novel fragment-based probe panel and developed a target prioritization scheme with improved stringency, which allows for the identification of unique target candidates, such as GSTZ1 in refractory lung cancer.

Surgical treatment of shoulder instability in active-duty service members with subcritical glenoid bone loss: Bankart vs. Latarjet.

INTRODUCTION: Subcritical bone loss has been identified as a risk factor for potentially inferior outcomes following typical arthroscopic soft tissue repair. One alternative that has been presented as an option for patients with bone loss is the Latarjet, an ipsilateral coracoid transfer to the anteroinferior glenoid. The purpose of this study is to compare the outcomes between the arthroscopic Bankart repair and the open Latarjet for the treatment of anterior shoulder instability in patients with subcritical bone loss. We hypothesize that the open Latarjet will provide higher patient-reported outcome measure scores and lower rates of dislocation. METHODS: A retrospective cohort comparison of patients with anterior glenohumeral instability procedures was performed. Inclusion criteria included symptomatic anterior shoulder instability, subcritical glenoid bone loss (13.5%-24%), surgical treatment with arthroscopic Bankart repair or open Latarjet, and minimum follow-up of 2 years. Outcomes included recurrent instability (defined as postoperative dislocation or subjective subluxation), permanent physical restrictions, Western Ontario Shoulder Index (WOSI), and Single Assessment Numeric Evaluation (SANE) scores. RESULTS: Forty-seven patients were included, 25 of whom underwent an arthroscopic Bankart repair and 23 patients an open Latarjet. The average bone loss was 17.8% and 19.3%, respectively. Overall, 8 patients experienced recurrent instability, 6 in the arthroscopic Bankart group and 2 in the open Latarjet group (P = .162). The average postoperative SANE score for arthroscopic Bankart group was 48% and for the open Latarjet group, 84% (P < .001). The average postoperative WOSI score for the arthroscopic Bankart group was 53.6% and for the open Latarjet group, 67.9% (P = .069). There were significantly more patients placed on permanent physical restrictions in the arthroscopic Bankart repair group (16) compared with open Latarjet (3) (P < .001). CONCLUSION: In patients with subcritical glenoid bone loss (defined as 13.5%-24%), patients treated with an open Latarjet have insignificantly higher SANE and WOSI scores and lower permanent physical restrictions than patients treated with an arthroscopic Bankart repair. We found no statistically significant difference in recurrent instability rates between the open Latarjet and arthroscopic Bankart repair (P = .162).

Can obese patients undergo simultaneous bilateral total knee arthroplasty without an increased risk of perioperative complications?

Simultaneous bilateral total knee arthroplasty (simBTKA) remains controversial, especially in obese patients. Therefore, this retrospective study compared six month perioperative complications in 313 simBTKA patients. Comparison groups included 139 non-obese patients (BMI < 30), 61 obese patients (BMI = 30-35) and 48 severely obese patients (BMI > 35). Increased BMI was associated with longer tourniquet and surgical times (p < 0.001). However, no differences were found for transfusion (p = 0.288), deep infection (p = 0.971), pulmonary embolism (p = 0.454), or deep vein thrombosis (p = 0.670). Increased BMI was, therefore, not associated with greater post-operative complications and should not necessarily contraindicate simBTKA.

Epidemiology and outcomes of obese critically ill patients in Australia and New Zealand.

OBJECTIVE: The apparent survival benefit of being overweight or obese in critically ill patients (the obesity paradox) remains controversial. Our aim is to report on the epidemiology and outcomes of obesity within a large heterogenous critically ill adult population. DESIGN: Retrospective observational cohort study. SETTING: Intensive care units (ICUs) in Australia and New Zealand. PARTICIPANTS: Critically ill patients who had both height and weight recorded between 2010 and 2018. OUTCOME MEASURES: Hospital mortality in each of five body mass index (BMI) strata. Subgroups analysed included diagnostic category, gender, age, ventilation status and length of stay. RESULTS: Data were available for 381 855 patients, 68% of whom were overweight or obese. Increasing level of obesity was associated with lower unadjusted hospital mortality: underweight (11.9%), normal weight (7.7%), overweight (6.4%), class I obesity (5.4%), and class II obesity (5.3%). After adjustment, mortality was lowest for patients with class I obesity (adjusted odds ratio, 0.78; 95% CI, 0.74- 0.82). Adverse outcomes with class II obesity were only seen in patients with cardiovascular and cardiac surgery ICU admission diagnoses, where mortality risk rose with progressively higher BMIs. CONCLUSION: We describe the epidemiology of obesity within a critically ill Australian and New Zealand population and confirm that some level of obesity is associated with lower mortality, both overall and across a range of diagnostic categories and important subgroups. Further research should focus on potential confounders such as nutritional status and the appropriateness of BMI in isolation as an anthropometric measure in critically ill patients.

Early perioperative complication rates and subsidence with the Tribute® short cementless, tapered stem in primary total hip arthroplasty.

This study examined early perioperative complications and subsidence following total hip arthroplasty (THA) with a short femoral stem. A retrospective review of 207 consecutive patients (247 hips) having undergone THA via the direct anterior approach produced only six perioperative complications: two intraoperative fractures, three perioperative femur fractures and one dislocation. Subsidence greater than 5 mm was observed in four hips but subsidence did not progress greater than 3 mm at the latest follow-up. Based on these results, cementless THA though the direct anterior approach with a short femoral stem provides a clinical and radiographic advantage while maintaining low complication rates.

Management of Cerebellar Tonsillar Herniation following Lumbar Puncture in Idiopathic Intracranial Hypertension.

Lumbar puncture is performed routinely for diagnostic and therapeutic purposes in idiopathic intracranial hypertension, despite lumbar puncture being classically contraindicated in the setting of raised intracranial pressure. We report the case of a 30-year-old female with known idiopathic intracranial hypertension who had cerebellar tonsillar herniation following therapeutic lumbar puncture. Management followed guidelines regarding treatment of traumatic intracranial hypertension, including rescue decompressive craniectomy. We hypothesize that the changes in brain compliance that are thought to occur in the setting of idiopathic intracranial hypertension are protective against further neuronal injury due to axonal stretch following decompressive craniectomy.