DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Utility of the sentinel node concept for detection of lateral pelvic lymph node metastasis in lower rectal cancer

Abstract Background There are two lymphatic flows in lower rectal cancer; one along the inferior mesenteric artery and another towards the internal iliac artery. The benefit of dissection of lateral pelvic (LP) lymph nodes (LPLN) remains controversial. This study aimed to clarify the possibility of detecting the sentinel node (SN) of the LP region (LPSN) and examine metastasis, including micrometastasis, using a radio isotope (RI) method. Methods In total, 62 patients with clinical (c)T1-T4 rectal cancer were enrolled in this study (11, 16 and 35 patients had tumor located in the upper, middle and lower rectal third, respectively). LPSNs were detected using a radio-isotope method in which 99 m technetium-tin colloid was endoscopically injected into the submucosa in patients with cT1, and into the muscularis propria in patients with cT2, cT3 and cT4. All patients underwent curative resection with lymphadenectomy. LPSN metastases were diagnosed by HE staining, immunohistochemical staining using AE1/AE3 as a primary antibody and by RT-PCR using CEA as a marker. Results Of the lower rectal (c)T2–4 tumors, 38.4% had lateral pelvic lymphatic flow that was significantly greater than that of cT1 tumors in the upper and middle thirds of the rectum (p = 0.0074). HE and immunohistochemical staining did not detect LPSN metastases but RT-PCR detected micrometastasis of three SNs. The remaining half of LPSNs were immunohistochemically re-examined; in all three cases, isolated tumor cells were detected. Conclusion The SN concept may be useful for detecting lateral pelvic lymphatic flow and LPSN metastases, including micrometastasis in lower rectal cancer

Three-stage laparoscopic surgery in a morbidly obese patient with Hinchey III diverticulitis: a case report

Abstract Background Perforated diverticulitis with purulent peritonitis (Hinchey III diverticulitis) has traditionally been treated with a Hartmann’s procedure in order to avoid the considerable postoperative morbidity and mortality associated with one-stage resection and primary anastomosis. Although there have been reports regarding laparoscopic lavage as the initial treatment of perforated Hinchey III diverticulitis, a formal treatment strategy has not been established yet. We performed a three-stage surgery, including laparoscopic lavage and drainage with diverting ileostomy (first stage), laparoscopic sigmoidectomy (second stage), and ileostomy closure (third stage) in a morbidly obese patient with Hinchey III diverticulitis. Case presentation A 31-year-old man who presented with abdominal pain was diagnosed with perforated diverticulitis and sent to our hospital for evaluation. He had morbid obesity (body mass index (BMI) 50 kg/m2), acute renal failure, and uncontrolled diabetes. We performed an emergency operation including laparoscopic lavage and drainage with a diverting ileostomy for this case of Hinchey III diverticulitis. Fifteen months after the first-stage surgery, we performed laparoscopic sigmoidectomy as the second stage. Finally, 5 months later, we performed ileostomy closure. The patient recovered without significant complications. Conclusion Three-stage surgery including early laparoscopic lavage and proximal diversion for morbidly obese, comorbid patients with Hinchey III diverticulitis may be indicated in the acute phase to avoid perioperative complications and permanent colostomy creation