Embryonal sarcoma of the liver in a girl with Cockayne syndrome.

The first reported malignancy associated with Cockayne syndrome.

Mechanisms of Resistance to KRASG12C Inhibitors.

KRAS is one of the most common human oncogenes, but concerted efforts to produce direct inhibitors have largely failed, earning KRAS the title of "undruggable". Recent efforts to produce subtype specific inhibitors have been more successful, and several KRASG12C inhibitors have reached clinical trials, including adagrasib and sotorasib, which have shown early evidence of efficacy in patients. Lessons from other inhibitors of the RAS pathway suggest that the effect of these drugs will be limited in vivo by the development of drug resistance, and pre-clinical studies of G12C inhibitors have identified evidence of this. In this review we discuss the current evidence for G12C inhibitors, the mechanisms of resistance to G12C inhibitors and potential approaches to overcome them. We discuss possible targets of combination therapy, including SHP2, receptor tyrosine kinases, downstream effectors and PD1/PDL1, and review the ongoing clinical trials investigating these inhibitors.

De novo DDX3X missense variants in males appear viable and contribute to syndromic intellectual disability.

DDX3X (Xp11.4) encodes a DEAD-box RNA helicase that escapes X chromosome inactivation. Pathogenic variants in DDX3X have been shown to cause X-linked intellectual disability (ID) (MRX102, MIM: 300958). The phenotypes associated with DDX3X variants are heterogeneous and include brain and behavioral abnormalities, microcephaly, hypotonia, and movement disorders and/or spasticity. The majority of DDX3X variants described are de novo mutations in females with ID. In contrast, most male DDX3X variants are inherited from an unaffected mother, with one documented exception being a recently identified de novo splice site variant. It has been suggested, therefore, that DDX3X exerts its effects through haploinsufficiency in females, and that affected males carry hypomorphic alleles that retain partial function. Given the lack of male de novo DDX3X variants, loss-of-function variants in this gene are suspected to be male lethal. Through whole-exome sequencing, we identified three unrelated males with hemizygous missense DDX3X variants and ID. All three variants were confirmed by Sanger sequencing, with two established as de novo. In silico analyses were supportive of pathogenicity. We report the male phenotypes and compare them to phenotypes observed in previously reported male and female patients. In conclusion, we propose that de novo DDX3X variants are not necessarily male lethal and should be considered as a cause of syndromic ID in both males and females.

How we did the Question Time Forum (QTF).

BACKGROUND: We piloted a new method of feedback to supplement online surveys and student representation. METHODS: The face-to-face feedback session enabled all Year 5 students to ask questions directly to a faculty panel, regarding their curriculum. Questions were gathered in advance so the panel could review and prepare appropriate responses. "Ask the audience" questions were also included. EVALUATION: The panel and a convenience sample of 25 students (attenders and non-attenders) were interviewed. All interviews were recorded, transcribed and themed using long table technique. QTF was also evaluated on-the-day by using "Ask the Audience" questions. RESULTS: Sixty-three Year 5 students attended (from a cohort of 337), of whom 96% felt it was a useful addition to current methods of feedback and 93% would attend again. Students felt QTF was "brilliant" and a "triumph in transparency" while the faculty hailed the "novel" event and "honest discussion". CONCLUSION: QTF was well-received by students and faculty. Both encouraged repetition of the event, thought to enhance the transparency of decisions about the running of the course and promote more in-depth dialogue between staff and students.