Robbferrell8529

Such tumor inhibition was absent in MAIT-deficient Mr1 -/- mice. CRISPR/Cas9-mediated MR1 knockout in tumor cells did not affect efficacy of this MAIT-directed immunotherapy, pointing toward an indirect mechanism of action. Our findings suggest that MAIT cells are an attractive target for cancer immunotherapy.See related Spotlight by Lantz.Adoptive transfer of genetically modified or donor-derived T cells can efficiently eradicate human tumors but is also frequently associated with major toxicity. There are several switches that can be used to kill the infused cell pool in the case of major toxicity, but the irreversible nature of these suicide switches means that the therapeutic effect is lost when they are used. To address this issue, we engineered a small-molecule responsive genetic safety switch that in the absence of drug robustly blocked cytotoxicity and cytokine expression of primary human T cells. Upon administration of drug, T-cell functions were restored in a reversible and titratable manner. We showed that this T-cell switch was universal, as it could be combined with endogenous or transduced T-cell receptors (TCR), as well as chimeric antigen receptors. The modular nature of the Chemically Regulated - SH2-delivered Inhibitory Tail (CRASH-IT) switch concept, in which inhibitory domains are brought to activating immune receptors in a controlled manner, makes it a versatile platform to regulate the activity of cell products that signal through immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors.

Changes in albuminuria or estimated glomerular filtration rate (eGFR) can be used as a surrogate endpoint of end-stage kidney disease (ESKD) in people with type 2 diabetes. We investigated whether the combined changes in albuminuria and eGFR are more strongly associated with future risk of ESKD.

Using data from a multicenter observational cohort study of people with type 2 diabetes, we evaluated the association of percentage change in urine albumin to creatinine ratio (UACR) and/or annual change in eGFR over 2 years with subsequent ESKD risk.

Among 1417 patients with repeated albuminuria and eGFR over 2 years, 129 (9.1%) developed ESKD. Patients with >30% UACR decline had lower ESKD risk (HR 0.47; 95% CI 0.29 to 0.77), whereas those with >30% UACR increase had higher ESKD risk (HR 2.31; 95% CI 1.52 to 3.51), compared with those with minor UACR change. Patients with greater eGFR decline had an increased ESKD risk than those with minor eGFR change (a decline of <2.5 mL/min/1.73 m

/year) HR 4.19 (95% CI 1.87 to 9.38) and 2.89 (95% CI 1.32 to 6.33) for those with a decline of >5 and 2.5-5 mL/min/1.73 m

/year, respectively. When the combined changes in UACR and eGFR were used, the highest ESKD risk (HR 5.60; 95% CI 2.08 to 15.09) was observed among patients with >30% UACR increase and an eGFR decline of >5 mL/min/1.73 m

/year compared with those with a minor change in UACR and eGFR.

Combined changes in albuminuria and eGFR over 2 years were strongly associated with future risk of kidney failure in patients with type 2 diabetes.

Combined changes in albuminuria and eGFR over 2 years were strongly associated with future risk of kidney failure in patients with type 2 diabetes.A 62-year-old woman presented with non-specific abdominal pain, elevated alkaline phosphatase levels and bilateral sequential visual loss. Visual acuity was counting fingers in right eye (RE) and 20/400 in left eye (LE). She was noted to have optic nerve pallor in RE and mildly elevated optic disc with signs of ocular inflammation in LE. After 2 weeks, vision deteriorated to light perception bilaterally with now extensive vitreal inflammation present in both eyes. Positive rapid plasma reagen and Treponema pallidum's antibody tites confirmed syphilis infection. Unfortunately, as the diagnosis was delayed by many months, her visual acuity remained poor (hand motions in RE and 20/50 in LE) despite treatment with intravenous penicillin. This case reminds us of the re-emergence of this 'great masquerader' and highlights the importance of maintaining high suspicion for syphilis in patients with unexplained visual loss and systemic symptoms, even in older adults without identifiable risk factors.Hypoparathyroidism is most often the result of postsurgical damage to the parathyroid glands but may occasionally be autoimmune hypoparathyroidism. In the latter context, activating antibodies directed against the calcium-sensing receptor (CaSR) have been described. We hereby present the case of a patient suffering from chronic recurrent muscle cramps and paresthesia, presenting for a seizure due to hypocalcaemia. After eliminating the possibility of a genetic disorder, we searched for autoimmune hypoparathyroidism as there was no obvious cause of hypoparathyroidism. The search for anti-CaSR antibodies was positive. There was no argument for autoimmune polyendocrine syndrome type 1 so we concluded that it was isolated autoimmune hypoparathyroidism caused by activating antibodies to the CaSR. The patient was treated with vitamin D and calcium supplementation. The search for complications of hypoparathyroidism and hypercalciuria revealed basal ganglia calcification. The patient's hypocalcaemia is now being kept under control with oral supplementation.Elevated plasma lipoprotein(a) is a relatively common condition that contributes to many cardiovascular diseases. However, the awareness and testing for this condition remain low. Herein, we present a case of an otherwise healthy and active man who developed symptoms of peripheral arterial disease starting at age 49, and was found to have hyper-lipoprotein(a) as his only notable risk factor. Diagnosis was not made until years later, after an extensive workup. Upon further screening, he was also found to have subclinical coronary and carotid artery atherosclerotic disease. The patient was treated with aspirin, statin, niacin and angioplasty to bilateral superficial femoral arteries with good symptom resolution. Epacadostat in vivo Early screening of his son also revealed a similarly elevated lipoprotein(a) level. It is important to raise awareness of this condition and its relationship to early-onset peripheral arterial disease so patients and their families can be appropriately identified, counselled and treated.