Notes

Consensus Affirmation on Alternative Management of Angina.
'Long COVID-19' can affect different body systems. At present, avascular necrosis (AVN) as a sequalae of 'long COVID-19' has yet not been documented. By large-scale use of life-saving corticosteroids in COVID-19 cases, we anticipate that there will be a resurgence of AVN cases. We report a series of three cases in which patients developed AVN of the femoral head after being treated for COVID-19 infection. The mean dose of prednisolone used in these cases was 758 mg (400-1250 mg), which is less than the mean cumulative dose of around 2000 mg steroid, documented in the literature as causative for AVN. Patients were symptomatic and developed early AVN presentation at a mean of 58 days after COVID-19 diagnosis as compared with the literature which shows that it generally takes 6 months to 1 year to develop AVN post steroid exposure.Subclavian artery injury is a rare complication of clavicle fracture. The fractured clavicle can lacerate the underlying subclavian artery. Life-threatening haemorrhage can occur secondary to arterial laceration, and if distal blood flow is impaired, upper limb ischaemia can develop. There is little discussion in the literature regarding combined (or 'hybrid') endovascular and open surgical management of acute subclavian injuries secondary to clavicle fracture. We report a case of subclavian artery laceration secondary to clavicle fracture, managed with a combined endovascular and open surgical approach. An endovascular balloon was used for proximal arterial control, while surgical exposure and primary repair of the subclavian artery was completed, followed by fixation of the clavicle. There was no sustained vascular or neurological impairment at follow-up. We suggest that select traumatic injuries of the subclavian artery can be safely and successfully managed with a combined endovascular and open surgical approach.We present the case of a 53-year-old woman with silicone breast implants who underwent excision of an abdominal melanoma and sentinel lymph node biopsy. Two lymph nodes were excised; both lying in the breast parenchyma adjacent to the intact right breast capsule. The lymph node histology revealed a subcapsular melanoma deposit along with silicone lymphadenopathy in the sentinel node. This case highlights that sentinel lymph nodes can be located in alternative locations to the common lymphatic basins and, therefore, the importance of preoperative lymphoscintigraphy. We also discuss subclinical breast implant rupture as a causative factor for silicone lymphadenopathy.Endometriosis is a benign estrogen-dependent disorder affecting women in their reproductive age group. Endometriosis means 'abnormal growth of endometrial glands' outside the uterus. Multiple theories on aetiopathogenesis of endometriosis have been postulated, Halban's theory on 'Benign Metastasis' which proposed the presence of endometriotic cells in lymphatic vessels and lymph nodes provides the basis of this case report. Here, we report a case of 26-year-old nulliparous woman who presented with grossly elevated CA 125 with endometriosis in her para-aortic nodes mimicking as ovarian cancer.We report a 7-month-old female infant who presented with anuric acute kidney injury and severe hyponatremia (serum sodium 110 mEq/L). The patient was treated with low-dose continuous kidney replacement therapy (CKRT), that is, 85% of total clearance dose divided equally between normonatric (Na 140 mEq/L) replacement and dialysate fluids. The remaining 15% of the clearance was provided by peripheral infusion of dextrose 5% (D5W). The patient's sodium was maintained between 119 mEq/L and 121 mEq/L for the first 24 hours of CKRT. Over the next 2 days, the rate of D5W infusion was slowly decreased while replacement and dialysis flow rates were proportionately increased. Serum sodium was normalised by day 2 of the therapy. The patient had no neurologic sequelae associated with this therapy.We report a fifth case of a transverse colon primary synovial sarcoma. A 31-year-old man with history of grade I obesity presented to an outpatient clinic reporting 6 months of intermittent colicky abdominal pain associated with haematochezia and rectal bleeding. Colonoscopy reported a partially obstructive intraluminal tumour lesion located in the transverse colon. There was no evidence of metastatic disease in the extension studies, so the patient was admitted to the hospital for a laparoscopic subtotal colectomy. Histopathology demonstrated intermediate-grade synovial sarcoma. At the third year of follow-up, the patient presented metastases on the chest wall, which required extensive resection and complementary oncological management.
To evaluate whether prestroke glucose control is associated with functional outcomes in patients with acute large vessel occlusive stroke and diabetes who underwent intra-arterial thrombectomy (IAT).

From the Clinical Research Center for Stroke-Korea registry, we included patients with emergent large vessel occlusive stroke with diabetes who underwent IAT between January 2009 and March 2020. The association between the HbA
level at admission and functional outcomes (modified Rankin Scale at 3 months after the index stroke) was assessed.

A total of 1,351 patients were analyzed. selleck products Early neurological deterioration was more common in patients with higher levels of HbA
at admission (
= 0.02 according to HbA
quintiles,
= 0.003 according to an HbA
cutoff value of 7.0%) than in those with lower HbA
levels. Higher HbA
levels at admission were significantly associated with decreased odds of favorable functional outcomes at a threshold of 7.0-7.1%. The association was consistently observed in subgroups divided according to age, sex, stroke subtype, occlusion site, degree of recanalization, thrombolysis modalities, time from symptom onset to groin puncture, and treatment period.

Prestroke glucose control with a target HbA
of ≤7.0% may be beneficial for neurological recovery in patients with diabetes undergoing IAT for large vessel occlusive stroke, regardless of stroke subtype, bridging intravenous thrombolysis, occlusion site, degree of recanalization, and treatment period.
Prestroke glucose control with a target HbA1c of ≤7.0% may be beneficial for neurological recovery in patients with diabetes undergoing IAT for large vessel occlusive stroke, regardless of stroke subtype, bridging intravenous thrombolysis, occlusion site, degree of recanalization, and treatment period.The fitness landscape of cancer clones was perturbed by mutation and treatment in vitro and in vivo.Colorectal cancer cells express hepcidin to accumulate iron, promoting nucleotide metabolism.HER3 missense mutations can inhibit response of tumor cells to HER2-targeted therapies.Pharmacologic inhibition of RNA splicing produces immunogenic neoepitopes driving T-cell expansion.We systematically reviewed and synthesized evidence on the impact of physical activity/exercise on cancer treatment efficacy. We included six preclinical and seven clinical studies. Exercise significantly enhanced the efficacy of chemotherapy and tamoxifen in seven of eight rodent models in either an additive, sensitizing, or synergistic manner. In clinical studies, preliminary evidence indicates that exercise during neoadjuvant, primary, and adjuvant treatment may enhance efficacy of cancer therapies; however, no clinical study was designed for this purpose. Here we discuss the biological mechanisms of exercise-associated enhancement of therapeutic efficacy and propose future research directions to definitively examine the effects of exercise on cancer treatment and patient outcomes.The somatic landscape of the cancer genome results from different mutational processes represented by distinct "mutational signatures." Although several mutagenic mechanisms are known to cause specific mutational signatures in cell lines, the variation of somatic mutational activities in patients, which is mostly attributed to somatic selection, is still poorly explained. Here, we introduce a quantitative trait, mutational propensity (MP), and describe an integrated method to infer genetic determinants of variations in the mutational processes in 3,566 cancers with specific underlying mechanisms. As a result, we report 2,314 candidate determinants with both significant germline and somatic effects on somatic selection of mutational processes, of which, 485 act via cancer gene expression and 1,427 act through the tumor-immune microenvironment. These data demonstrate that the genetic determinants of MPs provide complementary information to known cancer driver genes, clonal evolution, and clinical biomarkers. SIGNIFICANCE The genetic determinants of the somatic mutational processes in cancer elucidate the biology underlying somatic selection and evolution of cancers and demonstrate complementary predictive power across cancer types.The lack of knowledge about the relationship between tumor genotypes and therapeutic responses remains one of the most critical gaps in enabling the effective use of cancer therapies. Here we couple a multiplexed and quantitative experimental platform with robust statistical methods to enable pharmacogenomic mapping of lung cancer treatment responses in vivo. The complex map of genotype-specific treatment responses uncovered that over 20% of possible interactions show significant resistance or sensitivity. Known and novel interactions were identified, and one of these interactions, the resistance of KEAP1 mutant lung tumors to platinum therapy, was validated using a large patient response dataset. These results highlight the broad impact of tumor suppressor genotype on treatment responses and define a strategy to identify the determinants of precision therapies.Nonsense-mediated RNA decay (NMD) is recognized as an RNA surveillance pathway that targets aberrant mRNAs with premature translation termination codons (PTC) for degradation; however, its molecular mechanisms and roles in health and disease remain incompletely understood. In this study, we developed a novel reporter system to accurately measure NMD activity in individual cells. A genome-wide CRISPR-Cas9 knockout screen using this reporter system identified novel NMD-promoting factors, including multiple components of the SF3B complex and other U2 spliceosome factors. Interestingly, cells with mutations in the spliceosome genes SF3B1 and U2AF1, which are commonly found in myelodysplastic syndrome (MDS) and cancers, have overall attenuated NMD activity. Compared to wild type cells, SF3B1 and U2AF1 mutant cells were more sensitive to NMD inhibition, a phenotype that is accompanied by elevated DNA replication obstruction, DNA damage, and chromosomal instability. Remarkably, the sensitivity of spliceosome mutant cells to NMD inhibition was rescued by overexpression of RNase H1, which removes R-loops in the genome. Together, these findings shed new light on the functional interplay between NMD and RNA splicing and suggest a novel synthetic lethal strategy for the treatment of MDS and cancers with spliceosome mutations.Somatic variants in TET2 and DNMT3A are founding mutations in hematological malignancies that affect the epigenetic regulation of DNA methylation. Mutations in both genes often co-occur with activating mutations in oncogenic tyrosine kinases such as FLT3ITD, BCR-ABL1, JAK2V617F, and MPLW515L, or with mutations affecting related signaling pathways such as NRASG12D and CALRdel52. Here we show that TET2 and DNMT3A mutations exert divergent roles in regulating DNA repair activities in leukemia cells expressing these oncogenes. Malignant TET2-deficient cells displayed downregulation of BRCA1 and LIG4, resulting in reduced activity of BRCA1/2-mediated homologous recombination (HR) and DNA-PK -mediated non-homologous end-joining (D-NHEJ), respectively. TET2-deficient cells relied on PARP1-mediated alternative NHEJ (Alt-NHEJ) for protection from the toxic effects of spontaneous and drug-induced DNA double-strand breaks. Conversely, DNMT3A-deficient cells favored HR/D-NHEJ owing to downregulation of PARP1 and reduction of Alt-NHEJ.
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