Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor.

KRASG12C was recently identified to be potentially druggable by allele-specific covalent targeting of Cys-12 in vicinity to an inducible allosteric switch II pocket (S-IIP). Success of this approach requires active cycling of KRASG12C between its active-GTP and inactive-GDP conformations as accessibility of the S-IIP is restricted only to the GDP-bound state. This strategy proved feasible for inhibiting mutant KRAS in vitro; however, it is uncertain whether this approach would translate to in vivo. Here, we describe structure-based design and identification of ARS-1620, a covalent compound with high potency and selectivity for KRASG12C. ARS-1620 achieves rapid and sustained in vivo target occupancy to induce tumor regression. We use ARS-1620 to dissect oncogenic KRAS dependency and demonstrate that monolayer culture formats significantly underestimate KRAS dependency in vivo. This study provides in vivo evidence that mutant KRAS can be selectively targeted and reveals ARS-1620 as representing a new generation of KRASG12C-specific inhibitors with promising therapeutic potential.

Effects of a Clown-Nurse Educational Intervention on the Reduction of Postoperative Anxiety and Pain Among Preschool Children and Their Accompanying Parents in South Korea.

This study examined the effects of a clown-nurse educational intervention on children undergoing day surgery for strabismus. This was a quasi-experimental study, using a nonequivalent control group, non-synchronized design. Fifty preschool children and their parents were invited to participate. The children in the intervention group (n=23) received clown therapy and subsequently reported significantly lower states of physiological anxiety, which was evidenced by systolic blood pressure, standardized behavioral anxiety tests, and post-surgery pain, than the control group (n=27). In addition, the parents in the experimental group showed a low state of physiological anxiety, evidenced by systolic blood pressure, pulse rates, standardized behavioral anxiety tests, and state-trait anxiety. The use of preoperative clown intervention may alleviate postoperative problems, not only for children, but also for their parents.

Salvage optic nerve decompression for traumatic blindness under nasal endoscopy: risk and benefit analysis.

OBJECTIVES: Transnasal endoscopic optic nerve decompression was recommended to treat traumatic optic neuropathy as an effectively adjunctive procedure. The aim of this study was to assess the risks and benefits of salvage surgical decompression for complete vision loss (no light detection) after failure of mega-dose steroid therapy. DESIGN: Retrospective study. SETTING: Two hospitals in Guangzhou and Nanjing, China. PARTICIPANTS: Forty-two patients of traumatic optic neuropathy with complete vision loss and failed to improve after steroid therapy for at least 3 days. MAIN OUTCOME MEASURES: All patients were treated by transnasal endoscopic optic nerve decompression and received follow-up for at least 6 month. Vision improvement and complications were evaluated. RESULTS: Transnasal endoscopic optic nerve decompression was performed successfully in 40 patients and was incomplete in two patients due to bleeding. Vision improved in four of 42 patients (9.5%) of traumatic optic neuropathy with complete vision loss and failed steroid therapy. Complications and sequelae included severe bleeding (two cases), cerebrospinal fluid rhinorrhea (one case), nasal polyps (seven cases), chronic sinusitis (four cases) and nasal synechia (17 cases). CONCLUSION: Transnasal endoscopic optic nerve decompression was recommended as a minimally invasive, safe procedure, but complications and sequelae of the surgery should not be neglected. Based on the risk and benefit analysis, we conclude that the very poor surgical outcomes of this series do not support endoscopic optic nerve decompression for traumatic blindness.

Discovery of (R,E)-N-(7-Chloro-1-(1-[4-(dimethylamino)but-2-enoyl]azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide (EGF816), a Novel, Potent, and WT Sparing Covalent Inhibitor of Oncogenic (L858R, ex19del) and Resistant (T790M) EGFR Mutants for the Treatment of EGFR Mutant Non-Small-Cell Lung Cancers.

Over the past decade, first and second generation EGFR inhibitors have significantly improved outcomes for lung cancer patients with activating mutations in EGFR. However, both resistance through a secondary T790M mutation at the gatekeeper residue and dose-limiting toxicities from wild-type (WT) EGFR inhibition ultimately limit the full potential of these therapies to control mutant EGFR-driven tumors and new therapies are urgently needed. Herein, we describe our approach toward the discovery of 47 (EGF816, nazartinib), a novel, covalent mutant-selective EGFR inhibitor with equipotent activity on both oncogenic and T790M-resistant EGFR mutations. Through molecular docking studies we converted a mutant-selective high-throughput screening hit (7) into a number of targeted covalent EGFR inhibitors with equipotent activity across mutants EGFR and good WT-EGFR selectivity. We used an abbreviated in vivo efficacy study for prioritizing compounds with good tolerability and efficacy that ultimately led to the selection of 47 as the clinical candidate.

Conducting operational research within a non governmental organization: the example of Medecins Sans Frontieres.

Like many other non governmental organizations (NGOs) that provide assistance to vulnerable populations living in difficult and resource-limited settings, Médecins Sans Frontières (MSF) is confronted with situations for which proven, effective interventions are often lacking and/or where there is need for strong advocacy for improving medical care. As a result, MSF has become an important contributor to health research, and has dedicated resources to guide operational research by establishing its own Ethics Review Board, an innovation fund, an online publications repository and by regularly contributing to major scientific conferences. However, this increased research activity has led to concern that priorities and resources may be diverted away from the essential mandate of care provision for NGOs. In response, this article discusses the potential role operational research can play within medical NGOs such as MSF, and highlights the relevance of operational research, the essential elements of developing it within the organisation and some of the perceived barriers and solutions.

Surgical treatment of distal tibia fractures: a comparison of medial and lateral plating.

The surgical method of repairing distal tibial fractures remains controversial. Open reduction and plating is a popular method that can result in good fixation and retention of the achieved position. The usual approach for open plating is anterior. Although it offers good exposure to the tibia, the medial plating is at high risk of wound problems and nonunions. Also, if fixation of the fibula is required, an additional incision must be made on the lateral side of the shin. Lateral plating using a single lateral approach for treating distal tibial and fibular fractures has been reported to have good results; however, most of these studies were small series. We retrospectively evaluated and compared the clinical outcomes of distal tibial fractures treated with medial plating using an anterior approach and lateral plating using a lateral approach. Eighty-eight patients with distal tibial fractures treated with medial or lateral plating were retrospectively reviewed. The 88 fractures were divided into 2 groups: the medial plating group used an anterior approach and included 49 patients and the lateral plating group used a lateral approach and included 39 patients. Both groups were similar with respect to injury mechanism, union rate, malunion rate, operative time, functional score, and range of ankle motion (P>or=.14). Both medial and lateral plating for treating distal tibial fractures achieved good functional outcomes with a low malunion rate; however, the lateral plating group had a lower complication rate (P=.047) and fewer hardware problems (P<.001).

Novel adjunctive treatment for cervical adhesion with cross-type nelaton catheter: a preliminary report and literature review.

OBJECTIVE: Intrauterine adhesion remains a common complication post dilatation and curettage (D&C) in reproductive females. Internal cervical orifice adhesion (ICA) is also observed incidentally after D&C. Here, we introduce a novel adjunctive management for ICA with cross-type nelaton catheter. MATERIALS AND METHODS: In this study, 20 patients suffering from amenorrhea and ICA after D&C were included. All individuals underwent flexible hysteroscopy to confirm their simple ICA statuses. All women accepted the insertion of simple cross-type nelaton catheter. Two weeks post insertion, the catheter was removed and a second-look hysteroscopy was performed. Three months post catheter removal, the menstruation statuses and the efficiency of nelaton catheter in preventing ICA were evaluated. RESULTS: Nineteen patients had 3-month follow-up. Seventeen individuals (89.4%) had normal menstruation flow as well as the impact internal orifice of cervical canal. Only two patients (10.5%) had hypomenorrhea and fibrotic narrowing of the internal orifice of the cervix, which required resectoscopy to remove the internal cervical adhesions. All patients appeared the competence of endurance for these procedures. CONCLUSION: The novel cross-type nelaton catheter is a simple, well tolerated, and highly effective method for the management of ICA after D&C.

Environmental modulation of autoimmune arthritis involves the spontaneous microbial induction of T cell responses to regulatory determinants within heat shock protein 65.

Both genetic and environmental factors are believed to be involved in the induction of autoimmune diseases. Adjuvant arthritis (AA) is inducible in susceptible rat strains by injection of Mycobacterium tuberculosis, and arthritic rats raise T cell responses to the 65-kDa mycobacterial heat-shock protein (Bhsp65). We observed that Fischer 344 (F344) rats raised in a barrier facility (BF-F344) are susceptible to AA, whereas F344 rats maintained in a conventional facility (CV-F344) show significantly reduced incidence and severity of AA, despite responding well to the arthritogenic determinant within Bhsp65. The acquisition of protection from AA can be circumvented if rats are maintained on neomycin/acidified water. Strikingly, naive unimmunized CV-F344 rats but not BF-F344 rats raised T cell responses to Bhsp65 C-terminal determinants (BCTD) (we have previously shown that BCTD are involved in regulation of acute AA in the Lewis rat); however, T cells of naive CV-F344 and BF-F344 gave a comparable level of proliferative response to a mitogen, but no response at all to an irrelevant Ag. Furthermore, adoptive transfer into naive BF-F344 rats of splenic cells of naive CV-F344 rats (restimulated with BCTD in vitro) before induction of AA resulted in a considerably reduced severity of AA. These results suggest that spontaneous (inadvertent) priming of BCTD-reactive T cells, owing to determinant mimicry between Bhsp65 and its homologues in microbial agents in the conventional environment, is involved in modulating the severity of AA in CV-F344 rats. These results have important implications in broadening understanding of the host-microbe interaction in human autoimmune diseases.