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Lindgren Penn posted an update 6 months, 1 week ago
Lung squamous cell carcinoma (LSCC) is the second most prevalent type of lung cancer. Despite extensive genomic characterization, no targeted therapies are approved for the treatment of LSCC. Distal amplification of the 3q chromosome is the most frequent genomic alteration in LSCC, and there is an urgent need to identify efficacious druggable targets within this amplicon. We identify the protein kinase TNIK as a therapeutic target in LSCC. TNIK is amplified in approximately 50% of LSCC cases. TNIK genetic depletion or pharmacologic inhibition reduces the growth of LSCC cells in vitro and in vivo. In addition, TNIK inhibition showed antitumor activity and increased apoptosis in established LSCC patient-derived xenografts. Mechanistically, we identified the tumor suppressor Merlin/NF2 as a novel TNIK substrate and showed that TNIK and Merlin are required for the activation of focal adhesion kinase. selleck chemical In conclusion, our data identify targeting TNIK as a potential therapeutic strategy in LSCC. SIGNIFICANCE Targeted therapies have not yet been approved for the treatment of LSCC, due to lack of identification of actionable cancer drivers. We define TNIK catalytic activity as essential for maintaining LSCC viability and validate the antitumor efficacy of TNIK inhibition in preclinical models of LSCC.This article is highlighted in the In This Issue feature, p. 1307.
To identify root causes of preventable adverse drug events (pADEs) contributing to hospital admission; to develop key messages which identify actions patients/families and healthcare providers can take to prevent common pADEs found; to develop a surveillance learning system for the community.
Cross-sectional observational study; 120 patients and families, 61 associated healthcare providers were interviewed then root cause analysis was performed to develop key learning messages and an electronic reporting tool was designed. Most common pADE-related medical conditions and their root causes and most common pADE root causes of entire cohort are reported.
Most common pADE-related medical conditions chronic obstructive pulmonary disease/asthma (13.3%), bleeding (12.5%), hypotension (12%), heart failure (10%), acute kidney injury (5%) and pneumonia (5%). Most common root causes were providers not confirming that the patient/family understands information given (29.2%), can identify how a medication helps them/s should assess patient’s/families’ medication use and monitoring competency.Takotsubo cardiomyopathy (TCMP) is an important, though under-recognised, syndrome which mimics acute coronary syndrome (ACS) presenting with similar clinical, biochemical and ECG features. A 68-year-old man was referred as ACS for emergency coronary angiography; however, a history of lethargy, weight loss and electrolyte abnormalities prompted further investigations. Angiography was postponed, adrenal insufficiency confirmed and steroid replacement commenced. Echocardiography demonstrated reduced left ventricular (LV) function (45%) with regional wall motion abnormalities, although angiography confirmed unobstructed arteries. Steroid replacement induced a rapid improvement in symptoms and LV function. Few cases of TCMP associated with adrenal insufficiency have been reported. This appears to be the first case describing TCMP precipitated by new-onset secondary adrenal insufficiency following long-term steroid use in a male patient, and highlights the importance of considering TCMP in patients presenting with suspected ACS. Here, prompt recognition and treatment of a serious underlying disorder prevented a potentially life-threatening Addisonian crisis.Congenital knee dislocation is a rare condition of unknown aetiology. It could be associated with syndromes or may occur as an isolated entity. The severity of the deformity determines the method of treatment. Treatment options range from conservative casting to surgical correction. The case presented is of a newborn with an isolated grade II dislocation treated with serial casting. On follow-up at 2 years, the patient had a good outcome, with full range of motion and independent mobility.Conn’s syndrome is an important endocrine cause for secondary hypertension. Hypokalaemia paralysis and rhabdomyolysis with accelerated hypertension may be the presenting symptoms of Conn’s syndrome. Here, we present one such case of a 38-year-old woman presenting with accelerated hypertension and acute onset quadriplegia. On biochemical evaluation, she was found to have severe hypokalaemia, metabolic alkalosis and elevated creatinine phosphokinase. Further evaluation revealed an elevated aldosterone renin ratio suggestive of primary hyperaldosteronism which was localised to left adrenal adenoma on contrast-enhanced CT. Patient’s blood pressure and serum potassium levels normalised after resection of the adrenal adenoma.A 42-year-old man from rural India presented with asymmetric progressive paraparesis mimicking compressive dorsal myelopathy, followed by distal upper limb, truncal and neck-flexor weakness, further complicated by acute urinary retention. His sensory deficits were marked by loss of joint position sense (JPS) and graded loss of vibration sense, along with a definite sensory level. Deep tendon jerks were hypo-to-areflexic, plantar was bilaterally extensor. He had become less attentive and occasionally failed to keep track with conversations. A syndromic diagnosis of myeloradiculoneuropathy with cognitive impairments was made. Further tailored investigations revealed vitamin B12 deficiency with positive anti-parietal cell antibody. Diagnosis of subacute combined cord degeneration (SACD) was confirmed. Neuro-imaging revealed intramedullary intensity changes only along lateral aspect of spinal cord instead of characteristic posterior involvement. Following parenteral vitamin B12 supplementation, patient started showing improvement in motor power and subjective sensory symptoms. His bladder symptoms persisted initially, however recovered finally after 6 months.A 13-year-old boy sustained a superior pole patellar sleeve fracture after a blunt trauma of the knee. A medial patellofemoral ligament reconstruction had been performed 4 weeks earlier. The patient underwent surgery to reinsert the quadriceps tendon in the superior pole of the patella using two bone suture anchors. One-year postoperative assessment revealed excellent functional outcomes. Sleeve fractures are easily misdiagnosed, and in our case, clinical examination was essential in order to perform the diagnosis.
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