Interactions between cancer cells and immune cells drive transitions to mesenchymal-like states in glioblastoma

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Delivering end-of-life care for patients with cancer at home: Interviews exploring the views and experiences of general practitioners

Many patients with terminal cancer wish to die at home and general practitioners in the United Kingdom have a critical role in providing this care. However, it has been suggested general practitioners lack confidence in end-of-life care. It is important to explore with general practitioners their experience and perspectives including feelings of confidence delivering end-of-life care to people with cancer. The aim of this study was to explore general practitioners experiences of providing end-of-life care for people with cancer in the home setting and their perceptions of confidence in this role as well as understanding implications this has on policy design. A qualitative study design was employed using semi-structured interviews and analysed using thematic analysis. Nineteen general practitioners from London were purposively sampled from eight general practices and a primary care university department in 2018–2019, supplemented with snowballing methods. Five main themes were constructed: (a) the subjective nature of defining palliative and end-of-life care; (b) importance of communication and managing expectations; (c) complexity in prescribing; (d) challenging nature of delivering end-of-life care; (e) the unclear role of primary care in palliative care. General practitioners viewed end-of-life care as challenging; specific difficulties surrounded communication and prescribing. These challenges coupled with a poorly defined role created a spread in perceived confidence. Experience and exposure were seen as enabling confidence. Specialist palliative care service expansion had important implications on deskilling of essential competencies and reducing confidence levels in general practitioners. This feeds into a complex cycle of causation, leading to further delegation of care.     

Rapalogs induce non-apoptotic,autophagy-dependent cell death in HPV-negative TP53 mutant head and neck squamous cell carcinoma

TP53 is the most frequently mutated gene in head and neck squamous cell carcinoma (HNSCC). Patients with HPV-negative TP53 mutant HNSCC have the worst prognosis, necessitating additional agents for treatment. Since mutant p53 causes sustained activation of the PI3K/AKT/mTOR signaling pathway, we investigated the effect of rapalogs RAD001 and CCI-779 on HPV-negative mutTP53 HNSCC cell lines and xenografts. Rapalogs significantly reduced cell viability and colony formation. Interestingly, rapalogs-induced autophagy with no effect on apoptosis. Pretreatment with autophagy inhibitors, 3-methyladenine (3-MA) and ULK-101 rescued the cell viability by inhibiting rapalog-induced autophagy, suggesting that both RAD001 and CCI-779 induce non-apoptotic autophagy-dependent cell death (ADCD). Moreover, rapalogs upregulated the levels of ULK1 and pULK1 S555 with concomitant downregulation of the mTORC1 pathway. However, pretreatment of cells with rapalogs prevented the ULK-101-mediated inhibition of ULK1 to sustained autophagy, suggesting that rapalogs induce ADCD through the activation of ULK1. To further translate our in vitro studies, we investigated the effect of RAD001 in HPV-negative mutTP53 (HN31 and FaDu) tumor cell xenograft model in nude mice. Mice treated with RAD001 exhibited a significant tumor volume reduction without induction of apoptosis, and with a concomitant increase in autophagy. Further, treatment with RAD001 was associated with a considerable increase in pULK1 S555 and ULK1 levels through the inhibition of mTORC1. 3-MA reversed the effect of RAD001 on FaDu tumor growth suggesting that RAD001 promotes ACDC in HPV-negative mutTP53 xenograft. This is the first report demonstrating that rapalogs promote non-apoptotic ADCD in HPV-negative mutTP53 HNSCC via the ULK1 pathway. Further studies are required to establish the promising role of rapalogs in preventing the regrowth of HPV-negative mutTP53 HNSCC.     

Delusional parasitosis as presenting symptom of occipital lobe cerebrovascular accident

Delusional parasitosis manifests as a fixed, false belief that an individual is infested by living organisms. Primary delusional parasitosis is a psychiatric disorder with the delusion as an isolated manifestation, whereas secondary delusional parasitosis is a delusion occurring secondary to a psychiatric disorder, substance use, or medical illness. A 62-year-old woman with no psychiatric history presented to the Emergency Department with two to three months of “whole body itching” and seeing small insects crawling on her skin and in her hair. Exam of her skin and scalp was notable for no appreciable lesions, rashes, excoriations, or insects. Her neurologic exam was notable for full visual fields, and no localizing deficits. A non-contrast head CT demonstrated a nonspecific heterogeneous low-attenuation lesion within the medial right occipital lobe, and a follow up MRI confirmed a right posterior cerebral artery distribution subacute infarction. She was admitted for two days, and ultimately was discharged on aspirin and atorvastatin for secondary prevention. An emergency physician should remain vigilant in his/her assessment of patients with seemingly psychiatric symptoms, in particular elderly patients with no known psychiatric illnesses. Neuroimaging should be amongst studies considered in the evaluation of elderly patients presenting with new onset psychiatric complaints.     

Crowdsourced and crowdfunded: the future of forensic DNA?

ABSTRACT

Forensic DNA analysis is dependent on comparing the known and the unknown. Expand the number of known profiles, and the likelihood of a successful match increases. Forensic use of DNA is moving towards comparing samples of unknown origin with publicly available genetic data, such as the records held by genetic genealogy providers. Use of forensic genetic genealogy has yielded a number of recent high-profile successes but has raised ethical and privacy concerns. Navigating family trees is complex, even more so when combined with a comparison of genetic relationships. This intelligence-gathering process has led to occasional false leads, and its use also risks a public backlash, similar to concerns over Cambridge Analytica. A cautious approach to use of this technique is therefore warranted.     

Start-up propulsion biomechanics changes with fatiguing activity in persons with spinal cord injury

Objective: Shoulder pathology is a common condition in wheelchair users that can considerably impact quality of life. Shoulder muscles are prone to fatigue, but it is unclear how fatigue affects start-up propulsion biomechanics. This study determines acute changes in start-up wheelchair propulsion biomechanics at the end of a fatiguing propulsion protocol.

Design: Quasi-experimental one-group pretest-postest design.

Setting: Biomechanics laboratory. Participants: Twenty-six wheelchair users with spinal cord injury (age: 35.5?±?9.8 years, sex: 73% males and 73% with a paraplegia).

Interventions: Protocol of 15 min including maximum voluntary propulsion, right- and left turns, full stops, start-up propulsion, and rests.

Outcome measures: Maximum resultant force, maximum rate of rise of applied force, mean velocity, mean fraction of effective force, and mean contact time at the beginning and end of the protocol during start-up propulsion.

Results: There was a significant reduction in maximum resultant force (P?<?0.001) and mean velocity (P?<?0.001) at the end of the protocol. Also, contact time was reduced in the first stroke of start-up propulsion (P?<?0.001). Finally, propelling with a shorter contact time was associated with a greater reduction in performance (maximum velocity) at the end of the protocol.

Conclusion: There are clear changes in overground propulsion biomechanics at the end of a fatiguing propulsion protocol. While reduced forces could protect the shoulder, these reduced forces come with shorter contact times and lower velocity. Investigating changes in start-up propulsion biomechanics with fatigue could provide insight into injury risk.