Systemic Tissue and Cellular Disruption from SARS-CoV-2 Infection revealed in COVID-19 Autopsies and Spatial Omics Tissue Maps

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus has infected over 115 million people and caused over 2.5 million deaths worldwide. Yet, the molecular mechanisms underlying the clinical manifestations of COVID-19, as well as what distinguishes them from common seasonal influenza virus and other lung injury states such as Acute Respiratory Distress Syndrome (ARDS), remains poorly understood. To address these challenges, we combined transcriptional profiling of 646 clinical nasopharyngeal swabs and 39 patient autopsy tissues, matched with spatial protein and expression profiling (GeoMx) across 357 tissue sections. These results define both body-wide and tissue-specific (heart, liver, lung, kidney, and lymph nodes) damage wrought by the SARS-CoV-2 infection, evident as a function of varying viral load (high vs. low) during the course of infection and specific, transcriptional dysregulation in splicing isoforms, T cell receptor expression, and cellular expression states. In particular, cardiac and lung tissues revealed the largest degree of splicing isoform switching and cell expression state loss. Overall, these findings reveal a systemic disruption of cellular and transcriptional pathways from COVID-19 across all tissues, which can inform subsequent studies to combat the mortality of COVID-19, as well to better understand the molecular dynamics of lethal SARS-CoV-2 infection and other viruses.

Host, Viral, and Environmental Transcriptome Profiles of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused thousands of deaths worldwide, including >18,000 in New York City (NYC) alone. The sudden emergence of this pandemic has highlighted a pressing clinical need for rapid, scalable diagnostics that can detect infection, interrogate strain evolution, and identify novel patient biomarkers. To address these challenges, we designed a fast (30-minute) colorimetric test (LAMP) for SARS-CoV-2 infection from naso/oropharyngeal swabs, plus a large-scale shotgun metatranscriptomics platform (total-RNA-seq) for host, bacterial, and viral profiling. We applied both technologies across 857 SARS-CoV-2 clinical specimens and 86 NYC subway samples, providing a broad molecular portrait of the COVID-19 NYC outbreak. Our results define new features of SARS-CoV-2 evolution, nominate a novel, NYC-enriched viral subclade, reveal specific host responses in interferon, ACE, hematological, and olfaction pathways, and examine risks associated with use of ACE inhibitors and angiotensin receptor blockers. Together, these findings have immediate applications to SARS-CoV-2 diagnostics, public health, and new therapeutic targets.

Biological response of human esophageal squamous carcinoma cell line KYSE-150 to fractionated x-ray irradiation in vitro / 中华放射肿瘤学杂志

Objective To establish a radioresistant human cell line from esophageal squamous car-cinoma cells and detect the marker expression of cancer stem cells (CSCs). Methods A radioresistant hu-man esophageal squamous carcinoma cell line KYSE-150R was established by fractionated irradiation. Mor-phological changes from KYSE-150 to KYSE-150R were observed by phase- contrast microscopy. Karyotype analysis was performed by G-banding. The radiosensitivity of these two cell lines was assessed by colony for-marion assays. The cell cycle distribution was assayed by flow cytometry. CSCs markers of β-catenin and In-tegrin-β_1 were measured by Western Blot. Results The population doubling time of KYSE-150 and KYSE-150R were (23.62±0.23) hrand (25.90±0.55) hr, respectively (t =6.62,P=0.00). The numbers of chromosomes in KYSE-150R cells were increased and chromosome aberrations were observed. The SF_2, D_0, D_q and N values of KYSE-150R were all higher than those of KYSE-150. The ratio of D_0 values was 1.21. After irradiation, the number of S-phase cells of KYSE-150 increased from 45.35%±4.03% to 55.09%± 1.70% (t = -3.86,P=0.02) and G2/M phase cells decreased from 9.91%±3.83% to 1.15%±0.32% (t = 3.95, P = 0.02). However, no apparent change of cell cycle distribution for KYSE- 150R was observed. The expression levels of CSCs markers, β-catenin and Integrin-β_1 in KYSE-150R were about 2 times of those in KYSE-150. Conclusions The new cell line KYSE-150R is more radioresistant than its parental cell line KYSE-150. The CSCs in KYSE-150R is more than those in KYSE-150, which may suggest that CSCs is re-lated with the radioresistance.

Study on cancer-related fatigue of lung cancer patients receiving chemotherapy and its impact on the quality of life / 中国实用护理杂志

Objective To explore the incidence and severity of cancer-related fatigue (CRF),and to analyze the correlation between CRF and quality of life in lung cancer patients receiving chemotherapy.Methods This was a cross-sectional study.72 lung cancer patients receiving chemotherapy were investigated by the Piper Fatigue Scale (PFS) and the 36-item short form of the Medical Outcomes Study questionnaire (SF-36).Results The rate of fatigue for lung cancer patients receiving chemotherapy was 76.4%.The incidence of moderate and severe fatigue in total fatigue,behavior/severity dimension,affective dimension,sensory dimension was 68.1%,63.9%,76.4% and 65.3% respectively.The incidence of mild and moderate fatigue in coguitive/mood dimension was 41.7%.The fatigue dimension scores ranked in a descending order,affective,behavior/severity,sensory and cognitive/mood.There was significant negative correlation between CRF and quality of life for lung cancer patients receiving chemotherapy.Conclusions In lung cancer patients receiving chemotherapy,the incidence and degree of fatigue was high.CRF and QOL affect each other.The health care providers should take measures to alleviate lung cancer patients' fatigue in order to improve the QOL of them.

Postoperative radiotherapy concurrent with paclitaxel and cisplatin in the adjuvant treatment of gastric cancer:An analysis of 64 cases / 中国基层医药

Objective To evaluate the efficacy and toxicity of postoperative chemoradiation for D2 dissection gastric cancer,and to compare the difference of toxicity between confromal and traditional radiotherapy.Methods Sixty four patients with T3-4,N + or R1 were enrolled.Radioation was given to a total dose of 46Gy delivered in 23fractions by use of 3D-CRT or 4 fields traditional radiotherapy.Chemothrepy was administered with paclitaxel 135 mg/m2 day 1 and 29,cisplantin 20 mg/m2 day 1 ～3 and day 29 ～31 during radiotherapy.Results The median follow-up time was 40 months.The 3-year overall and relapse-free survival rates were 78.2% and 70.9%,respectively.Eighteen patients had tumor relapse.Fifty-three patients completed chemoradiotheray.Toxicities on grade 3 or above included gastrointestinal toxicity (28.1% ),eutropenia (21.8 % ) and alopecia ( 18.7% ).One patient died of hemorrhage of upper digestion tract.Conclusion Adjuvant radiotherapy with paclitaxol and cisplatin yielded satisfactory overall survival and disease-free survival in gastric cancer patients.The toxicity was manageable.Conformal radiotherapy seems to decrease the gastrointestinal toxicities compared to that occurred in the traditional radiotherapy.

Cetuximab enhances the radiosensitivity of radioresistant human esophageal squamous carcinoma cell line KYSE-150R / 中华放射医学与防护杂志

Objective To determine the effect of cetuximab(C225)on the radioresistant human esophageal squamous carcinoma eell line KYSE-150R.Methods A radioresistant human esophageal squamous carcinoma cell line KYSE-150R was established by fractionated irradiation.Morphological changes from KYSE-150 to KYSE-150R were observed by phase-contrast microscopy.Karyotype analysis was performed by G-banding.The radiosensitivities were analyzed by colony formation assays.Results The population doubling time of KYSE-150 and KYSE-150R were(23.6±0.2)h and(25.9±0.6)h (t=6.6,P<0.01),respectively.The chromosome number of KYSE-150R was increased and chromosome aberrations were observed from(69.3±1.9)h to(73.7±1.2)h(t=-8.83,P<0.01).The SF2,D0,Dq and N values of KYSE-150R were all higher than those of KYSE-150.After 5μg/ml of C225 added,the SF2,D0,Dq and N values were significantly decreased as compared to the control.After C225 treatment,the G0/G1 and G2/M phase cells were increased,while S-phase cells decreased(t=-4.478-4.308,P<0.05).Conclusion Cetuximab can enhance the radiosensitivity of radioresistant human esophageal squamous carcinoma cell line KYSE-150R.

Technical and dosimetric considerations in multi-isocenter intensity modulated radiotherapy for nasopharyngeal carcinoma with small multileaf collimator.

Multileaf collimator (MLC)-assisted intensity modulated radiotherapy (IMRT) has greatly improved the target coverage and avoidance of organs at risk (OAR) for the treatment of nasopharyngeal carcinoma; however, its implementation is also constrained by the features of the MLC. Nasopharyngeal carcinoma tends to have a large gross target volume (GTV) and clinical target volume (CTV) due to its biological characteristics. More than one isocenter may be needed when small MLCs (i.e., BrainLAB M3, whose largest field is 10 x 10 cm(2)) are used to treat the nasopharyngeal carcinoma. The BrainLAB IMRT system was used to evaluate the effectiveness of a multi-isocenter IMRT plan for treating nasopharyngeal cancers. Dose coverage of GTVs and CTVs were compared among IMRT plans with 1, 2 and 3 isocenters, as were dose objectives for OARs including brainstem, cord, and parotids. The dosimetric variation and the delivery time were also measured with a phantom. IMRT plans with more than 1 isocenter achieved a better dose coverage, homogeneity, and conformity on GTVs and CTVs; however, with risk of higher doses given to OARs. In most cases, one can generate satisfactory IMRT plans using the 2-isocenter IMRT planning strategy. Two-isocenter planning strategy may be a suitable compromise when more isocenters are needed.

A application study of dose constraint template in intensity modulated radiation therapy planning for early stage nasopharyngeal carcinoma / 中华放射医学与防护杂志

Objective To investigate a feasibility of using dose constraint template (DCT) to increase conformity index (CI) of planning target volume (PTV) and improve intensity modulated radiation therapy (IMRT) planning efficiency for early stage nasopharyngeal carcinoma. Methods Ten patients with pathological diagnosed and treated by IMRT were selected for this study. Target volumes were delineated with Corvus 6.3 of treatment planning system, two dose limiting regions(DLR) around PIN were added by extending from PIN,each DLR was 1 cm thick. We created three plans:Plan0,Planl and Plan2. PianO was without DLR and DCT, Planl without DLR but with DCT, Plan2 with both condition;but to compare dose distribution in PLTV and normal tissue using three plans. Results Three plans could fill equal request of dose distribution in PLTV and normal tissue, and their difference was not statistical significant. CI of Plan2 was increased and planning time was decreased significantly compared with Piano and Planl. Conclusloa Usage of DCT together with DLR can increase CI of PTV and improve IMRT planning efficiency for early stage nasopharyngeal carcinoma, planning time is shortened significantly.

Effect of Kanglaite Combined with Chemical Therapy Advanced Non-small Cell Lung Cancer / 中国药房

OBJECTIVE:To study the effect of Kanglaite combined with chemical therapy on advanced non-small cell lung cancer.METHODS:70 patients were randomly divided into treatment group and control group(n=35).Both groups were given GP regime of chemical therapy.Treatment group were additionally treated with Kanglaite.Clinical efficacy,quality of life and adverse reactions of 2 groups were observed.RESULTS:Recent response rate were 54.29% for treatment group and 37.14% for control group,there were statistical significance in difference between 2 groups(P

Concurrent chemoradiation therapy with cisplatin and paclitaxel for locally advanced non-small cell lung cancer / 中华放射肿瘤学杂志

Objective To evaluate the efficacy of concurrent systemic routine dose of paclitaxel/ cisplatin combined with conventional thoracie irradiation in locally advanced non-small cell lung cancer(NSCLC).Methods Forty-two unresectable stage ⅢA and ⅢB NSCLC patients were entered into this study.All patients received conventional thoracic irradiation to a total dose of 60Gy within 6 weeks,with concurrent paclitaxel 135mg/m~2,d1,and cisplatin 75mg/m~2 in the first and fourth week of radiotherapy.Results The complete response(CR) and partial response(PR) was 2/42,and 30/42 patients,with an overall response rate of 76.2% and a median survival time of 18 months.The 1-,2-,and 3-year survival rate was 64.3%,30.2%,12.0%,respectively.The 1-,2-,and 3-year progression-free survival rates was 48.1%,21.4%,5.7%,with a median progression-free survival of 12 months.Fourteen patients failed only locoregionally,10 in distant metastastasis only and 5 in both.The locoregional/distant failure rate was higher in stageⅢB than in stage ⅢA(P

A technical study of radiotherapy after surgery for gastric carcinoma / 中国癌症杂志

Purpose:To evaluate the safety and efficacy of the box-shape field technique of radiotherapy for postoperative gastric carcinoma.Methods:Thirty-two patients of gastric carcinoma after subtotal or total gastrectomy with an extensive (D2) lymph-node dissection were irradiated with a total dose of 46～50Gy Gy of external box-shape field technical in 23-25 fractions by linac with 6-MV photons. All patients received concomitant chemotherapy which two cycles of paclitaxel (135mg/m~2 ) and cisplatin (70mg/m~2) in d1-3 and d29-31.Results:The overall survival,the relapse free survival of two years of all patients was 87.50% and 16.67%, respectively. 32 patients with treatment failure had recurrent disease, 4 (6.3%)in the liver,2(6.3%) in the peritoneum, 2(12.5%) in the anastomosis ,respectively. the plan of box-shape fields were evaluated with dose-volume histogram of three-dimensional therapy plan system, The 90% isodose line included the whole clinical target volume,and the dose of organat at rist was under the tolerance dose, except the dose of left kidney.Conclusions:The box-shape field technique of radiotherapy for postoperative gastric carcinoma were a technique which the dose distribution of clinical target volume was satisfaction ,and well tolerated with no severe side effects.[

Expression of Fas/FasL in lung cancer and its significance / 中国癌症杂志

Purpose:To study the expression and significance of Fas/FasL in lung cancer.Methods:The expression of Fas/FasL was detected in 42 cases of non-small-cell lung cancer by immunohistochemistry. Results:Out of 42 cases, Fas was positive in 22 cases (52.3%) and FasL was positive in 24 cases(57.1%), there was no correlation between the expression of Fas and FasL. The expression of Fas/FasL was not different in squamous cell carcinoma and adenocarcinoma. The stage of lung cancer had a positive correlation with the expression of FasL, while was no correlation with Fas expression.Conclusions:The expression of Fas/FasL in lung cancer may play an important role in the escape of tumor cells from immune function and FasL is worthy of further research in metastasis of lung neoplasms.

Intensify modulated radiotherapy (IMRT) for nasopharyngeal carcinoma / 中华放射肿瘤学杂志

Objective To evaluate the feasibility, toxicity and clinical efficacy of simultaneous modulated accelerated radiation therapy(SMART)for nasopharyngeal carcinoma. Methods Thirty eight patients with nasopharyngeal carcinoma were treated by SMART with 2.5?Gy/fraction at gross tumor volume(GTV)to a total dose of 70?Gy and 2.0?Gy/fraction at the clinical treatment volume(CTV)to a total dose of 56?Gy in 38 days. Quantitative 99m Tc pertechnetate salivary scintigraphy was used to assess the uptake and excretion index (EI、UI) of parotid gland in order to validate the value of IMRT in parotid gland sparing. Results The mean doses delivered to the GTV and CTV were 67.2?Gy and 57.0?Gy, respectively. An average of 1% of GTV and 2% of CTV received less than 90% or 95% of the prescribed dose. The mean dose to the contralateral parotid were 23?Gy and no significant decline in EI and UI as compared with significant decline in the ipsilateral parotid by 43.6% and 26.3%(P