Hepatocellular Carcinoma: Current Management and Future Development—Improved Outcomes with Surgical Resection

Currently, surgical resection is the treatment strategy offering the best long-term outcomes in patients with hepatocellular carcinoma (HCC). Especially for advanced HCC, surgical resection is the only strategy that is potentially curative, and the indications for surgical resection have expanded concomitantly with the technical advances in hepatectomy. A major problem is the high recurrence rate even after curative resection, especially in the remnant liver. Although repeat hepatectomy may prolong survival, the suitability may be limited due to multiple tumor recurrence or background liver cirrhosis. Multimodality approaches combining other local ablation or systemic therapy may help improve the prognosis. On the other hand, minimally invasive, or laparoscopic, hepatectomy has become popular over the last decade. Although the short-term safety and feasibility has been established, the long-term outcomes have not yet been adequately evaluated. Liver transplantation for HCC is also a possible option. Given the current situation of donor shortage, however, other local treatments should be considered as the first choice as long as liver function is maintained. Non-transplant treatment as a bridge to transplantation also helps in decreasing the risk of tumor progression or death during the waiting period. The optimal timing for transplantation after HCC recurrence remains to be investigated

Warm and Dense Molecular Gas in the N159 Region: 12CO J=4-3 and 13CO J=3-2 Observations with NANTEN2 and ASTE

New 12CO J=4-3 and 13CO J=3-2 observations of the N159 region in the Large Magellanic Cloud have been made. The 12CO J=4-3 distribution is separated into three clumps. These new measurements toward the three clumps are used in coupled calculations of molecular rotational excitation and line radiation transfer, along with other transitions of the 12CO as well as the isotope transitions of 13CO. The temperatures and densities are determined to be ~70-80K and ~3x10^3 cm-3 in N159W and N159E and ~30K and ~1.6x10^3 cm-3 in N159S. These results are compared with the star formation activity. The N159E clump is associated with embedded cluster(s) as observed at 24 micron and the derived high temperature is explained as due to the heating by these sources. The N159E clump is likely responsible for a dark lane in a large HII region by the dust extinction. The N159W clump is associated with embedded clusters mainly toward the eastern edge of the clump only. These clusters show offsets of 20"-40" from the 12CO J=4-3 peak and are probably responsible for heating indicated by the derived high temperature. The N159W clump exhibits no sign of star formation toward the 12CO J=4-3 peak position and its western region. We suggest that the N159W peak represents a pre-star-cluster core of ~105M_sol which deserves further detailed studies. Note that recent star formation took place between N159W and N159E as indicated by several star clusters and HII regions, while the natal molecular gas toward the stars have already been dissipated by the ionization and stellar winds of the OB stars. The N159S clump shows little sign of star formation as is consistent with the lower temperature and somewhat lower density. The N159S clump is also a candidate for future star formation

Dense Clumps in Giant Molecular Clouds in the Large Magellanic Cloud: Density and Temperature Derived from 13^{13}CO(J=3−2J=3-2) Observations

In order to precisely determine temperature and density of molecular gas in the Large Magellanic Cloud, we made observations of optically thin $^{13}$CO($J=3-2$) transition by using the ASTE 10m telescope toward 9 peaks where $^{12}$CO($J=3-2$) clumps were previously detected with the same telescope. The molecular clumps include those in giant molecular cloud (GMC) Types I (with no signs of massive star formation), II (with HII regions only), and III (with HII regions and young star clusters). We detected $^{13}$CO($J=3-2$) emission toward all the peaks and found that their intensities are 3 -- 12 times lower than those of $^{12}$CO($J=3-2$). We determined the intensity ratios of $^{12}$CO($J=3-2$) to $^{13}$CO($J=3-2$), $R^{12/13}_{3-2}$, and $^{13}$CO($J=3-2$) to $^{13}$CO($J=1-0$), $R^{13}_{3-2/1-0}$, at 45\arcsec resolution. These ratios were used for radiative transfer calculations in order to estimate temperature and density of the clumps. The parameters of these clumps range kinetic temperature $T\mathrm{_{kin}}$ = 15 -- 200 K, and molecular hydrogen gas density $n(\mathrm{H_2})$ = 8$\times 10^2$ -- 7$\times 10^3$ cm$^{-3}$. We confirmed that the higher density clumps show higher kinetic temperature and that the lower density clumps lower kinetic temperature at a better accuracy than in the previous work. The kinetic temperature and density increase generally from a Type I GMC to a Type III GMC. We interpret that this difference reflects an evolutionary trend of star formation in molecular clumps. The $R^{13}_{3-2/1-0}$ and kinetic temperature of the clumps are well correlated with H$\alpha$ flux, suggesting that the heating of molecular gas $n(\mathrm{H_2})$ = $10^3$ -- $10^4$ cm$^{-3}$ can be explained by stellar FUV photons.Comment: 39 pages, 7 figures, 4 tables. Accepted for publication in The Astronomical Journa

Sub-millimeter Observations of Giant Molecular Clouds in the Large Magellanic Cloud: Temperature and Density as Determined from J=3-2 and J=1-0 transitions of CO

We have carried out sub-mm 12CO(J=3-2) observations of 6 giant molecular clouds (GMCs) in the Large Magellanic Cloud (LMC) with the ASTE 10m sub-mm telescope at a spatial resolution of 5 pc and very high sensitivity. We have identified 32 molecular clumps in the GMCs and revealed significant details of the warm and dense molecular gas with n(H2) $\sim$ 10$^{3-5}$ cm$^{-3}$ and Tkin $\sim$ 60 K. These data are combined with 12CO(J=1-0) and 13CO(J=1-0) results and compared with LVG calculations. We found that the ratio of 12CO(J=3-2) to 12CO(J=1-0) emission is sensitive to and is well correlated with the local Halpha flux. We interpret that differences of clump propeties represent an evolutionary sequence of GMCs in terms of density increase leading to star formation.Type I and II GMCs (starless GMCs and GMCs with HII regions only, respectively) are at the young phase of star formation where density does not yet become high enough to show active star formation and Type III GMCs (GMCs with HII regions and young star clusters) represents the later phase where the average density is increased and the GMCs are forming massive stars. The high kinetic temperature correlated with \Halpha flux suggests that FUV heating is dominant in the molecular gas of the LMC.Comment: 74 pages, including 41 figures, accepted for publication in ApJ

Review of juxtaglomerular cell tumor with focus on pathobiological aspect

Juxtaglomerular cell tumor (JGCT) generally affects adolescents and young adults. The patients experience symptoms related to hypertension and hypokalemia due to renin-secretion by the tumor. Grossly, the tumor is well circumscribed with fibrous capsule and the cut surface shows yellow or gray-tan color with frequent hemorrhage. Histologically, the tumor is composed of monotonous polygonal cells with entrapped normal tubules. Immunohistochemically, tumor cells exhibit a positive reactivity for renin, vimentin and CD34. Ultrastructurally, neoplastic cells contain rhomboid-shaped renin protogranules. Genetically, losses of chromosomes 9 and 11 were frequently observed. Clinically, the majority of tumors showed a benign course, but rare tumors with vascular invasion or metastasis were reported. JGCT is a curable cause of hypertensive disease if it is discovered early and surgically removed, but may cause a fatal outcome usually by a cerebrovascular attack or may cause fetal demise in pregnancy. Additionally, pathologists and urologists need to recognize that this neoplasm in most cases pursues a benign course, but aggressive forms may develop in some cases

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

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