Publications by authors named "Imran Ahmad"

256 Publications

Cytotoxicity of Moringa oleifera fruits on human liver cancer and molecular docking analysis of bioactive constituents against caspase-3 enzyme.

J Food Biochem 2021 Apr 15:e13720. Epub 2021 Apr 15.

King Abdullah Institute for Nanotechnology, King Saud University, Riyadh, Saudi Arabia.

Moringa oleifera is an excellent source of phenolics and flavonoids comprise various pharmacological activities. The fourth widespread leading cause of the patients' death is liver cancer. This study was formulated to perform the antiproliferative activity of Moringa oleifera fruit (MOF) extract on human liver cancer HepG2 cells and computational validation of cell death. HepG2 cell line was treated with 25, 50, 75, 100, and 200 µg/ml of MOF extract for 48 hr, and antiproliferative activity was analyzed using MTT assay, nuclear condensation, annexin V-FITC/PI double stain, ROS generation, and apoptosis executioner enzyme caspase-3. MOF extract reduced the cell viability significantly (p ˂ .05) by increasing cellular apoptosis which was confirmed by annexin V-FITC/PI staining assay. In addition, MOF stimulated intracellular ROS production and subsequently induced caspase-3 activity depending upon dose. In silico analysis revealed the good binding interaction between amino acid residues of caspase-3 (PDB ID: 1GFW) protein and selected active constituents of MOF. PASS analyses of the phytoconstituents showed no violation of Lipinski's rule of five. Analysis of drug-likeness and toxicity measurement exhibited drug-like candidates with no predicted toxicity. In conclusion, this study showed the potential anticancer activity of MOF extract which may be valuable source for anticancer drug development. PRACTICAL APPLICATIONS: Moringa oleifera fruit extract induced the anti-proliferative activity against human hepatocellular carcinoma HepG2 cells through ROS-mediated apoptosis and activation of caspase-3 enzyme. Structure-based virtual screening study between bioactive components of Moringa oleifera fruits and apoptosis executioner caspase-3 enzyme has validated the anti-proliferative activity of Moringa oleifera fruit extract. Interestingly, active phytoconstituents of Moringa oleifera fruit exhibited drug-like candidates with no predicted toxicity. Thus, Moringa oleifera fruit could be used as valuable source for anticancer drug development against human liver cancer with relatively non-toxic to healthy cells.
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http://dx.doi.org/10.1111/jfbc.13720DOI Listing
April 2021

Emergency Airway Management in Patients with COVID-19: A Prospective International Multicenter Cohort Study.

Anesthesiology 2021 Apr 13. Epub 2021 Apr 13.

Background: Tracheal intubation for patients with COVID-19 is required for invasive mechanical ventilation. The authors sought to describe practice for emergency intubation, estimate success rates and complications, and determine variation in practice and outcomes between high-income and low- and middle-income countries. The authors hypothesized that successful emergency airway management in patients with COVID-19 is associated with geographical and procedural factors.

Methods: The authors performed a prospective observational cohort study between March 23, 2020, and October 24, 2020, which included 4,476 episodes of emergency tracheal intubation performed by 1,722 clinicians from 607 institutions across 32 countries in patients with suspected or confirmed COVID-19 requiring mechanical ventilation. The authors investigated associations between intubation and operator characteristics, and the primary outcome of first-attempt success.

Results: Successful first-attempt tracheal intubation was achieved in 4,017/4,476 (89.7%) episodes, while 23 of 4,476 (0.5%) episodes required four or more attempts. Ten emergency surgical airways were reported-an approximate incidence of 1 in 450 (10 of 4,476). Failed intubation (defined as emergency surgical airway, four or more attempts, or a supraglottic airway as the final device) occurred in approximately 1 of 120 episodes (36 of 4,476). Successful first attempt was more likely during rapid sequence induction versus non-rapid sequence induction (adjusted odds ratio, 1.89 [95% CI, 1.49 to 2.39]; P < 0.001), when operators used powered air-purifying respirators versus nonpowered respirators (odds ratio, 1.60 [95% CI, 1.16 to 2.20]; P = 0.006), and when performed by operators with more COVID-19 intubations recorded (odds ratio, 1.03 for each additional previous intubation [95% CI, 1.01 to 1.06]; P = 0.015). Intubations performed in low- or middle-income countries were less likely to be successful at first attempt than in high-income countries (odds ratio, 0.57 [95% CI, 0.41 to 0.79]; P = 0.001).

Conclusions: The authors report rates of failed tracheal intubation and emergency surgical airway in patients with COVID-19 requiring emergency airway management, and identified factors associated with increased success. Risks of tracheal intubation failure and success should be considered when managing COVID-19.

Editor’s Perspective:
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http://dx.doi.org/10.1097/ALN.0000000000003791DOI Listing
April 2021

Early hematological indicators of severe COVID-19 disease in hospitalized patients: Data from a South Asian population.

Int J Lab Hematol 2021 Apr 9. Epub 2021 Apr 9.

Section of Hematology, Department of Pathology, Shifa International Hospital, Islamabad, Pakistan.

Introduction: Outbreak of corona virus disease in 2019 (COVID-19) has resulted in significant morbidity and mortality worldwide. Our aim is to document hematological parameters of patients with COVID-19 during initial stage of diagnosis and to identify early hematological indicators of severe infection.

Materials And Methods: This retrospective study was conducted at Shifa International Hospital, Pakistan from April to November 2020. Patients hospitalized with COVID-19, diagnosed on RT-PCR and had a complete blood count (CBC) done within 48 hours of diagnosis were included. Data was analyzed using IBM SPSS Statistics.

Results: A total of 425 patients were included in this study out of whom 272(64%) were males. The mean age was 55.61 ± 17.84 years. 95 patients (22.4%) had normal blood counts within 48 hours of COVID-19 diagnosis. Cytopenias were seen in 193(45.4%) patients. There were 75(17.6%) mortalities during the study period. Chi-square test showed that thrombocytopenia, lymphopenia and neutrophilic leucocytosis were significantly associated with mortality (P = .037, P < .001, P < .001 respectively) and need for ventilator (P = .009, P < .001, P < .001, respectively). Neutrophilia was also associated with development of Acute Respiratory Distress Syndrome (P < .001). On ROC analysis, Neutrophil-to-Lymphocyte Ratio yielded an area under the curve (AUC) of 0.693 and 0.660 for the outcomes mortality and need for ventilator, respectively. For a subset of 288 patients who had D-dimer levels checked within 48 hours of COVID-19 diagnosis, the AUC for mortality and ventilator need was 0.708 and 0.671, respectively.

Conclusion: Hematological indices are vital indicators in the prognosis and risk stratification of COVID-19 during initial stages of disease.
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http://dx.doi.org/10.1111/ijlh.13533DOI Listing
April 2021

Gastroenteropancreatic neuroendocrine tumours: Clinicopathological evaluation at Shifa International Hospital, Islamabad.

J Pak Med Assoc 2021 02;71(2(A)):492-496

Department of Pathology, Shifa International Hospital, Islamabad, Pakistan.

Objective: Clinicopathological features of gastroenteropancreatic neuroendocrine tumours (GEP-NETs) have rarely been studied in Pakistani population. We investigated clinical characteristics of these tumours according to updated World Health Organization (WHO) 2010 classification.

Methods: The data of Shifa International Hospital, Islamabad was retrospectively analysed for pathologically confirmed GEP-NETs from January 2013 to March 2018.

Results: One hundred and eighteen patients (mean age, 52.2± 16.4 years; Of these 65(55.1%) were males. Majority, 98(83.1%) of the patients were symptomatic including 6(5.1%) with functional tumours. Pancreas was the most frequent primary site noted in 33(28%) patients. The most common histologic type was well differentiated neuroendocrine tumour (WDNET) in 96(81.4%) patients followed by neuroendocrine carcinoma (NEC) in 11(16.1%) patients. Almost half the cases or 54(45.8%) of WDNET were grade 1, 32 (27.1%) were grade 2, and 10 (8.5%) were grade 3. Distant metastasis at the time of diagnosis was found in 18(15.3%) cases with 14,(77.7%) in liver as the most common metastatic site. Synaptophysin positivity was seen in 60 (96.8%) cases of grade 1, 32(27.2%) of grade 2 WDNET, 8(100%) cases of grade 3 WDNET and 12(92.3%) of NEC and chromogranin was positive in 49(94.2%) of grade 1 and grade 2 WDNET, 5 (83.3%) cases of grade 3 WDNET and 5 (45.4%) cases of NEC.

Conclusions: GEP-NETs showed a wide clinicopathological spectrum. Pancreas is the most common site of involvement by the GEP-NET, however, grade 3 WDNET had a predilection for colon. Small cell carcinoma was commonly observed in the oesophagus.
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http://dx.doi.org/10.47391/JPMA.835DOI Listing
February 2021

Letter to the Editor: "Docetaxel and its nanoformulations: how delivery strategies could impact the therapeutic outcome?"

Ther Deliv 2021 Mar 29. Epub 2021 Mar 29.

Jina Pharmaceuticals Inc., Libertyville, IL 60048, USA.

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http://dx.doi.org/10.4155/tde-2020-0120DOI Listing
March 2021

Thymoquinone with Metformin Decreases Fasting, Post Prandial Glucose, and HbA1c in Type 2 Diabetic Patients.

Drug Res (Stuttg) 2021 Mar 8. Epub 2021 Mar 8.

Jina Pharmaceuticals Inc., Libertyville, IL, USA.

Objective: Antihyperglycemic activity of Thymoquinone (TQ) was evaluated in diabetic mouse model and patients.

Methods: TQ (50 mg/kg) was orally administered daily for 21 days in combination with metformin in diabetic mice and a reduction on blood glucose level was monitored. In human, a 90-day randomized study was carried out in 60 Type 2 Diabetes mellitus patients to evaluate safety and efficacy of TQ administration with metformin in a 3-arm study. Patients in arm 1 (T1) received 1 tablet of metformin SR 1000 mg and 1 tablet of TQ 50 mg once daily. The second arm (T2) patients received 1 tablet of metformin SR 1000 mg and 2 tablets of TQ 50 mg once daily. Patients in arm 3 (R) received 1 tablet of metformin SR 1000 mg only.

Results: The diabetic mice treated with combination of TQ and metformin showed significant decrease in blood sugar compared to those treated with only metformin. In patients who completed the study, the glycated hemoglobin (HbA1c) values in T1, T2 and R decreased after 3 months from 7.2, 7.2 and 7.3 to 6.7, 6.8, and 7.1, respectively. A greater reduction in Fasting Blood Glucose and Post Prandial Blood Glucose was also observed in T1 and T2 arms compared to R.

Conclusion: At dose levels of 50 and 100 mg of TQ combined with a daily dose of 1000 mg Metformin demonstrated a reduction in the levels of HbA1c and blood glucose compared to the standard treatment of diabetic patients with metformin alone.
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http://dx.doi.org/10.1055/a-1388-5415DOI Listing
March 2021

PPAR-gamma induced AKT3 expression increases levels of mitochondrial biogenesis driving prostate cancer.

Oncogene 2021 Apr 2;40(13):2355-2366. Epub 2021 Mar 2.

Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow, G61 1BD, UK.

Peroxisome Proliferator-Activated Receptor Gamma (PPARG) is one of the three members of the PPAR family of transcription factors. Besides its roles in adipocyte differentiation and lipid metabolism, we recently demonstrated an association between PPARG and metastasis in prostate cancer. In this study a functional effect of PPARG on AKT serine/threonine kinase 3 (AKT3), which ultimately results in a more aggressive disease phenotype was identified. AKT3 has previously been shown to regulate PPARG co-activator 1 alpha (PGC1α) localisation and function through its action on chromosome maintenance region 1 (CRM1). AKT3 promotes PGC1α localisation to the nucleus through its inhibitory effects on CRM1, a known nuclear export protein. Collectively our results demonstrate how PPARG over-expression drives an increase in AKT3 levels, which in turn has the downstream effect of increasing PGC1α localisation within the nucleus, driving mitochondrial biogenesis. Furthermore, this increase in mitochondrial mass provides higher energetic output in the form of elevated ATP levels which may fuel the progression of the tumour cell through epithelial to mesenchymal transition (EMT) and ultimately metastasis.
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http://dx.doi.org/10.1038/s41388-021-01707-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016665PMC
April 2021

healthcareCOVID: a national cross-sectional observational study identifying risk factors for developing suspected or confirmed COVID-19 in UK healthcare workers.

PeerJ 2021 4;9:e10891. Epub 2021 Feb 4.

Department of Anaesthesia, Guy's and St Thomas' NHS Foundation Trust, London, UK.

Objective: To establish the prevalence, risk factors and implications of suspected or confirmed coronavirus disease 2019 (COVID-19) infection among healthcare workers in the United Kingdom (UK).

Design: Cross-sectional observational study.

Setting: UK-based primary and secondary care.

Participants: Healthcare workers aged ≥18 years working between 1 February and 25 May 2020.

Main Outcome Measures: A composite endpoint of laboratory-confirmed diagnosis of SARS-CoV-2, or self-isolation or hospitalisation due to suspected or confirmed COVID-19.

Results: Of 6,152 eligible responses, the composite endpoint was present in 1,806 (29.4%) healthcare workers, of whom 49 (0.8%) were hospitalised, 459 (7.5%) tested positive for SARS-CoV-2, and 1,776 (28.9%) reported self-isolation. Overall, between 11,870 and 21,158 days of self-isolation were required by the cohort, equalling approximately 71 to 127 working days lost per 1,000 working days. The strongest risk factor associated with the presence of the primary composite endpoint was increasing frequency of contact with suspected or confirmed COVID-19 cases without adequate personal protective equipment (PPE): 'Never' (reference), 'Rarely' (adjusted odds ratio 1.06, (95% confidence interval: [0.87-1.29])), 'Sometimes' (1.7 [1.37-2.10]), 'Often' (1.84 [1.28-2.63]), 'Always' (2.93, [1.75-5.06]). Additionally, several comorbidities (cancer, respiratory disease, and obesity); working in a 'doctors' role; using public transportation for work; regular contact with suspected or confirmed COVID-19 patients; and lack of PPE were also associated with the presence of the primary endpoint. A total of 1,382 (22.5%) healthcare workers reported lacking access to PPE items while having clinical contact with suspected or confirmed COVID-19 cases.

Conclusions: Suspected or confirmed COVID-19 was more common in healthcare workers than in the general population and is associated with significant workforce implications. Risk factors included inadequate PPE, which was reported by nearly a quarter of healthcare workers. Governments and policymakers must ensure adequate PPE is available as well as developing strategies to mitigate risk for high-risk healthcare workers during future COVID-19 waves.
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http://dx.doi.org/10.7717/peerj.10891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868068PMC
February 2021

A COVID-19 Supply Chain Management Strategy Based on Variable Production under Uncertain Environment Conditions.

Int J Environ Res Public Health 2021 02 9;18(4). Epub 2021 Feb 9.

Department of Mechanical Engineering, Imperial College London, Exhibition Rd., London SW7 1AY, UK.

The management of a controllable production in the manufacturing system is essential to achieve viable advantages, particularly during emergency conditions. Disasters, either man-made or natural, affect production and supply chains negatively with perilous effects. On the other hand, flexibility and resilience to manage the perpetuated risks in a manufacturing system are vital for achieving a controllable production rate. Still, these performances are strongly dependent on the multi-criteria decision making in the working environment with the policies launched during the crisis. Undoubtedly, health stability in a society generates ripple effects in the supply chain due to high demand fluctuation, likewise due to the Coronavirus disease-2019 (COVID-19) pandemic. Incorporation of dependent demand factors to manage the risk from uncertainty during this pandemic has been a challenge to achieve a viable profit for the supply chain partners. A non-linear supply chain management model is developed with a controllable production rate to provide an economic benefit to the manufacturing firm in terms of the optimized total cost of production and to deal with the different situations under variable demand. The costs in the model are set as fuzzy to cope up with the uncertain conditions created by lasting pandemic. A numerical experiment is performed by utilizing the data set of the multi-stage manufacturing firm. The optimal results provide support for the industrial managers based on the proactive plan by the optimal utilization of the resources and controllable production rate to cope with the emergencies in a pandemic.
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http://dx.doi.org/10.3390/ijerph18041662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916223PMC
February 2021

Continuity of illicit drug use among Malay patients attending methadone clinics in Kelantan, Malaysia.

J Ethn Subst Abuse 2021 Jan 21:1-15. Epub 2021 Jan 21.

Department of Family Medicine, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.

The study aimed to determine the prevalence of continuity of illicit drug use and its associated factors among Malay opioid users receiving methadone treatment in Kelantan, Malaysia. This cross-sectional study involved a total of 150 respondents. Sociodemographic characteristic of participants, level of religiosity, and quality of life were collected using the self-administered questionnaires. The prevalence of continuity illicit drug use was 38.7% ( = 58) by self-report and 40.7% ( = 61) by positive urine test result for drugs. Positive hepatitis C status and high quality of life in the psychological health domain were associated with low continuity of illicit drug use by self-reported data and urine drug test results. In conclusion, the continuity of illicit drug use among methadone program users is still high, especially among those on methadone therapy for less than 2 years.
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http://dx.doi.org/10.1080/15332640.2021.1871696DOI Listing
January 2021

Major Urological Cancer Surgery for Patients is Safe and Surgical Training Should Be Encouraged During the COVID-19 Pandemic: A Multicentre Analysis of 30-day Outcomes.

Eur Urol Open Sci 2021 Mar 9;25:39-43. Epub 2021 Jan 9.

Division of Surgery and Interventional Science, University College London, London, UK.

COVID-19 has resulted in the deferral of major surgery for genitourinary (GU) cancers with the exception of cancers with a high risk of progression. We report outcomes for major GU cancer operations, namely radical prostatectomy (RP), radical cystectomy (RC), radical nephrectomy (RN), partial nephrectomy (PN), and nephroureterectomy performed at 13 major GU cancer centres across the UK between March 1 and May 5, 2020. A total of 598 such operations were performed. Four patients (0.7%) developed COVID-19 postoperatively. There was no COVID-19-related mortality at 30 d. A minimally invasive approach was used in 499 cases (83.4%). A total of 228 cases (38.1%) were described as training procedures. Training case status was not associated with a higher American Society of Anesthesiologists (ASA) score ( =  0.194) or hospital length of stay (LOS;  >  0.05 for all operation types). The risk of contracting COVID-19 was not associated with longer hospital LOS ( =  0.146), training case status ( =  0.588), higher ASA score ( =  0.295), or type of hospital site ( =  0.303). Our results suggest that major surgery for urological cancers remains safe and training should be encouraged during the ongoing COVID-19 pandemic provided appropriate countermeasures are taken. These real-life data are important for policy-makers and clinicians when counselling patients during the current pandemic.

Patient Summary: We collected outcome data for major operations for prostate, bladder, and kidney cancers during the COVID-19 pandemic. These surgeries remain safe and training should be encouraged during the ongoing pandemic provided appropriate countermeasures are taken. Our real-life results are important for policy-makers and clinicians when counselling patients during the COVID-19 pandemic.
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http://dx.doi.org/10.1016/j.euros.2021.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796655PMC
March 2021

A Multicentric, Retrospective Efficacy and Safety Study of Nanosomal Docetaxel Lipid Suspension in Metastatic Castration-Resistant Prostate Cancer.

Prostate Cancer 2020 24;2020:4242989. Epub 2020 Nov 24.

Jina Pharmaceuticals Inc., Libertyville, Illinois 60048, USA.

Purpose: To evaluate the efficacy and safety of nanosomal docetaxel lipid suspension (NDLS, DoceAqualip) in patients with metastatic castration-resistant prostate cancer (mCRPC).

Materials And Methods: In this multicenter, retrospective study, we analyzed the medical charts of mCRPC patients, who were treated with NDLS administered as 2-weekly (50 mg/m) or 3-weekly regimens (75 mg/m). The study endpoints were prostate-specific antigen (PSA) response (>50% PSA decline from baseline), PSA progression (PSA increase from baseline beyond 12 weeks: ≥25% and ≥2 ng/mL), median PSA decline, and time-to-treatment failure (TTF). Overall survival (OS) and safety were also evaluated.

Results: Data of 24 patients with mCRPC were analyzed in this study. NDLS was administered as a 2-weekly regimen in 37.5% (9/24; all first-line) patients and as a 3-weekly regimen in 62.5% patients (15/24; first-line: 20% (3/15), second-line: 80% (12/15)). Overall, PSA response was reported in 66.7% (16/24) patients. The PSA response was 77.8% (7/9 patients) in the 2-weekly group and 60% (9/15 patients) in the 3-weekly group. The median decline in PSA was 96.31% in the 2-weekly group and 83.29% in the 3-weekly group; the median TTF was 6.7 and 6.5 months in the 2 weekly group and 3-weekly group, respectively. The median OS was 14.6 months (follow-up: 5.5-25.8 months) in the 2-weekly group whereas it was not reached in the 3-weekly group (follow-up: 7.9-15.6 months). The most common hematological AEs were anemia, lymphopenia, thrombocytopenia, and neutropenia whereas nausea, weakness, constipation, vomiting, and diarrhea were the most common (≥10%) nonhematological AEs. Overall, NDLS treatment was well tolerated without any new safety concerns.

Conclusions: Nanosomal docetaxel lipid suspension (2-weekly or 3-weekly) was effective and well tolerated in patients with metastatic castration-resistant prostate cancer.
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http://dx.doi.org/10.1155/2020/4242989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758141PMC
November 2020

Endoxifen: A new, protein kinase C inhibitor to treat acute and mixed mania associated with bipolar I disorder.

Bipolar Disord 2020 Dec 25. Epub 2020 Dec 25.

Jina Pharmaceuticals Inc, Libertyville, IL, USA.

Objectives: Endoxifen is a protein kinase C inhibitor. The objective of the present phase III study was to demonstrate the safety and efficacy of endoxifen in treating bipolar I disorder (BPD I) patients.

Methods: A multicenter, double-blind, active-controlled study was conducted using a daily dose of 8 mg endoxifen compared to 1000 mg divalproex, the current standard treatment, in patients with BPD I acute manic episodes with/without mixed features. The primary endpoint of our study was the mean change in total Young Mania Rating Scale (YMRS) score at day 21.

Results: Endoxifen (n = 116) significantly (p < 0.0001) reduced total YMRS score (from 33.1 to 17.8. A significant (p < 0.001) improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) score was observed for endoxifen (4.8 to 2.5). Early time to remission of the disease was observed with endoxifen compared to divalproex. None of the patients required rescue medication and there was no drug-associated withdrawals. Changes in Clinical Global Impressions-Bipolar Disorder and Clinical Global Impression-Severity of Illness scores showed that treatment with endoxifen was well-tolerated.

Conclusions: Endoxifen at a low daily dose of 8 mg was as efficacious and safe in patients with BPD I acute manic episodes with/without mixed features.
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http://dx.doi.org/10.1111/bdi.13041DOI Listing
December 2020

Long Non-coding RNAs RN7SK and GAS5 Regulate Macrophage Polarization and Innate Immune Responses.

Front Immunol 2020 9;11:604981. Epub 2020 Dec 9.

Mucosal Immunology Lab, College of Dentistry, University of Illinois at Chicago, Chicago, IL, United States.

Macrophages (M) are immune cells that exhibit remarkable functional plasticity. Identification of novel endogenous factors that can regulate plasticity and innate immune functions of M will unravel new strategies to curb immune-related diseases. Long non-coding RNAs (lncRNAs) are a class of endogenous, non-protein coding, regulatory RNAs that are increasingly being associated with various cellular functions and diseases. Despite their ubiquity and abundance, lncRNA-mediated epigenetic regulation of M polarization and innate immune functions is poorly studied. This study elucidates the regulatory role of lncRNAs in monocyte to M differentiation, M1/M2 dichotomy and innate immune responses. Expression profiling of eighty-eight lncRNAs in monocytes and differentiated M2 M identified seventeen differentially expressed lncRNAs. Based on fold-change and significance, we selected four differentially expressed lncRNAs , RN7SK, GAS5, IPW, and ZFAS1 to evaluate their functional impact. LncRNA knockdown was performed on day 3 M2 M and the impact on polarization was assessed on day 7 by surface marker analysis. Knockdown of RN7SK and GAS5 showed downregulation of M2 surface markers (CD163, CD206, or Dectin) and concomitant increase in M1 markers (MHC II or CD23). RN7SK or GAS5 knockdown showed no significant impact on CD163, CD206, or CD23 transcripts. M1/M2 markers were not impacted by IPW or ZFAS1 knockdown. Functional regulation of antigen uptake/processing and phagocytosis, two central innate immune pathways, by candidate lncRNA was assessed in M1/M2 M. Compared to scramble, enhanced antigen uptake and processing were observed in both M1/M2 M transfected with siRNA targeting GAS5 and RN7SK but not IPW and ZFAS1. In addition, knockdown of RN7SK significantly augmented uptake of labelled by M1/M2 M, while no significant difference was in GAS5 silencing cells. Together, our results highlight the instrumental role of lncRNA (RN7SK and GAS5)-mediated epigenetic regulation of macrophage differentiation, polarization, and innate immune functions.
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http://dx.doi.org/10.3389/fimmu.2020.604981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757381PMC
December 2020

CCL25 and CCR9 is a unique pathway that potentiates pannus formation by remodeling RA macrophages into mature osteoclasts.

Eur J Immunol 2021 Apr 25;51(4):903-914. Epub 2021 Jan 25.

Jesse Brown VA Medical Center, Chicago, IL, USA.

This study elucidates the mechanism of CCL25 and CCR9 in rheumatoid arthritis (RA). RA synovial fluid (SF) expresses elevated levels of CCL25 compared to OA SF and plasma from RA and normal. CCL25 was released into RA SF by fibroblasts (FLS) and macrophages (MΦs) stimulated with IL-1β and IL-6. CCR9 is also presented on IL-1β and IL-6 activated RA FLS and differentiated MΦs. Conversely, in RA PBMCs neither CCL25 nor CCR9 are impacted by 3-month longitudinal TNF inhibitor therapy. CCL25 amplifies RA FLS and monocyte infiltration via p38 and ERK phosphorylation. CCL25-stimulated RA FLS secrete potentiated levels of IL-8 which is disrupted by p38 and ERK inhibitors. CCL25 polarizes RA monocytes into nontraditional M1 MΦs that produce IL-8 and CCL2. Activation of p38 and ERK cascades are also responsible for the CCL25-induced M1 MΦ development. Unexpectedly, CCL25 was unable to polarize RA PBMCs into effector Th1/Th17 cells. Consistently, lymphokine like RANKL was uninvolved in CCL25-induced osteoclastogenesis; however, this manifestation was regulated by osteoclastic factors such as RANK, cathepsin K (CTSK), and TNF-α. In short, we reveal that CCL25/CCR9 manipulates RA FLS and MΦ migration and inflammatory phenotype in addition to osteoclast formation via p38 and ERK activation.
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http://dx.doi.org/10.1002/eji.202048681DOI Listing
April 2021

Smoking Genes: A Case-Control Study of Dopamine Transporter Gene () and Dopamine Receptor Genes (, and ) Polymorphisms and Smoking Behaviour in a Malay Male Cohort.

Biomolecules 2020 12 3;10(12). Epub 2020 Dec 3.

Department of Family Medicine, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia.

Dopamine receptor and dopamine transporter genes polymorphisms have been associated with cigarette smoking behaviour in different populations. The aim of this case-control study was to evaluate polymorphisms in the dopamine transporter gene ( (rs27072)) and the dopamine receptor genes ( (rs686), (rs1800497) and (rs7653787)) and their contribution to smoking behaviour in a Malay male population. We identified 476 participants over the age of 18 years comprising 238 smokers and 238 non-smokers. Information such as age, height, weight, body mass index, systolic and diastolic blood pressures, marital status, and smoking status of close family members were taken. For the genetic study, we genotyped four genes ( (rs27072), (rs686), (rs1800497) and (rs7653787)) using the polymerase chain reaction-restriction fragment length polymorphism method and further confirmed our findings with sequencing. Dopamine receptor genes (, and ) were found to be associated with smoking behaviour in a Malay male population. The dopamine transporter gene () did not show this association. Significant differences were observed between smokers' and non-smokers' age, systolic blood pressure, marital status and family members who smoke. Smoking behaviour is significantly influenced by genetic variations of , and in a Malay male population.
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http://dx.doi.org/10.3390/biom10121633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761729PMC
December 2020

Timing of Tracheostomy for Prolonged Respiratory Wean in Critically Ill Coronavirus Disease 2019 Patients: A Machine Learning Approach.

Crit Care Explor 2020 Nov 17;2(11):e0279. Epub 2020 Nov 17.

Department of Critical Care, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom.

Objectives: To propose the optimal timing to consider tracheostomy insertion for weaning of mechanically ventilated patients recovering from coronavirus disease 2019 pneumonia. We investigated the relationship between duration of mechanical ventilation prior to tracheostomy insertion and in-hospital mortality. In addition, we present a machine learning approach to facilitate decision-making.

Design: Prospective cohort study.

Setting: Guy's & St Thomas' Hospital, London, United Kingdom.

Patients: Consecutive patients admitted with acute respiratory failure secondary to coronavirus disease 2019 requiring mechanical ventilation between March 3, 2020, and May 5, 2020.

Interventions: Baseline characteristics and temporal trends in markers of disease severity were prospectively recorded. Tracheostomy was performed for anticipated prolonged ventilatory wean when levels of respiratory support were favorable. Decision tree was constructed using C4.5 algorithm, and its classification performance has been evaluated by a leave-one-out cross-validation technique.

Measurements And Main Results: One-hundred seventy-six patients required mechanical ventilation for acute respiratory failure, of which 87 patients (49.4%) underwent tracheostomy. We identified that optimal timing for tracheostomy insertion is between day 13 and day 17. Presence of fibrosis on CT scan (odds ratio, 13.26; 95% CI [3.61-48.91]; ≤ 0.0001) and Pao:Fio ratio (odds ratio, 0.98; 95% CI [0.95-0.99]; = 0.008) were independently associated with tracheostomy insertion. Cox multiple regression analysis showed that chronic obstructive pulmonary disease (hazard ratio, 6.56; 95% CI [1.04-41.59]; = 0.046), ischemic heart disease (hazard ratio, 4.62; 95% CI [1.19-17.87]; = 0.027), positive end-expiratory pressure (hazard ratio, 1.26; 95% CI [1.02-1.57]; = 0.034), Pao:Fio ratio (hazard ratio, 0.98; 95% CI [0.97-0.99]; = 0.003), and C-reactive protein (hazard ratio, 1.01; 95% CI [1-1.01]; = 0.005) were independent late predictors of in-hospital mortality.

Conclusions: We propose that the optimal window for consideration of tracheostomy for ventilatory weaning is between day 13 and 17. Late predictors of mortality may serve as adverse factors when considering tracheostomy, and our decision tree provides a degree of decision support for clinicians.
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http://dx.doi.org/10.1097/CCE.0000000000000279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673767PMC
November 2020

Efficacy and safety of nanosomal docetaxel lipid suspension-based chemotherapy in squamous cell carcinoma of the head and neck: A multicenter retrospective study.

Oncol Lett 2020 Dec 8;20(6):344. Epub 2020 Oct 8.

Jina Pharmaceuticals Inc., Libertyville, IL 60048, USA.

Squamous cell carcinoma of the head and neck (SCCHN) is the most common cancer in Indian men. Docetaxel alone or in combination with other chemotherapeutic agents is recommended for the management of SCCHN. The present multicenter, retrospective study was conducted to evaluate the efficacy and safety of a novel docetaxel formulation 'nanosomal docetaxel lipid suspension (NDLS)'-based chemotherapy in SCCHN. The medical records of patients with SCCHN, who were treated with NDLS-based chemotherapy and followed up between August 2014 and September 2018, were reviewed. The efficacy endpoints were overall response rate [ORR; complete response (CR) + partial response (PR)] and disease control rate (DCR; CR + PR + stable disease) for patients receiving NDLS-based induction or palliative chemotherapy. Overall survival (OS) and safety were also evaluated. Efficacy evaluation was available in 30/34 patients (induction, 20/23; palliative, 10/11). NDLS-based induction chemotherapy showed an ORR and DCR of 95% and a median OS of 43.5 months (follow-up duration, 0.6-80.3 months). For NDLS-based palliative chemotherapy, the ORR and DCR were 50% and the median OS time was 4.6 months (follow-up duration, 1.8 to 14.3 months). At least one adverse event was reported in 82.6% patients. No new safety concerns were reported. Overall, NDLS-based chemotherapy was effective and well tolerated in the treatment of SCCHN.
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http://dx.doi.org/10.3892/ol.2020.12207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583840PMC
December 2020

The "Is mpMRI Enough" or IMRIE Study: A Multicentre Evaluation of Prebiopsy Multiparametric Magnetic Resonance Imaging Compared with Biopsy.

Eur Urol Focus 2020 Oct 10. Epub 2020 Oct 10.

Imperial Prostate, Division of Surgery, Department of Surgery and Cancer, Imperial College London, London, UK; Imperial Urology, Imperial College Healthcare NHS Trust, London, UK.

Background: Multiparametric magnetic resonance imaging (mpMRI) is now recommended prebiopsy in numerous healthcare regions based on the findings of high-quality studies from expert centres. Concern remains about reproducibility of mpMRI to rule out clinically significant prostate cancer (csPCa) in real-world settings.

Objective: To assess the diagnostic performance of mpMRI for csPCa in a real-world setting.

Design, Setting, And Participants: A multicentre, retrospective cohort study, including men referred with raised prostate-specific antigen (PSA) or an abnormal digital rectal examination who had undergone mpMRI followed by transrectal or transperineal biopsy, was conducted. Patients could be biopsy naïve or have had previous negative biopsies.

Outcome Measurements And Statistical Analysis: The primary definition for csPCa was International Society of Urological Pathology (ISUP) grade group (GG) ≥2 (any Gleason ≥7); the accuracy for other definitions was also evaluated.

Results And Limitations: Across ten sites, 2642 men were included (January 2011-November 2018). Mean age and PSA were 65.3yr (standard deviation [SD] 7.8yr) and 7.5ng/ml (SD 3.3ng/ml), respectively. Of the patients, 35.9% had "negative MRI" (scores 1-2); 51.9% underwent transrectal biopsy and 48.1% had transperineal biopsy, with 43.4% diagnosed with csPCa overall. The sensitivity and negative predictive value (NPV) for ISUP GG≥2 were 87.3% and 87.5%, respectively. The NPVs were 87.4% and 88.1% for men undergoing transrectal and transperineal biopsy, respectively. Specificity and positive predictive value of MRI were 49.8% and 49.2%, respectively. The sensitivity and NPV increased to 96.6% and 90.6%, respectively, when a PSA density threshold of 0.15ng/ml/ml was used in MRI scores 1-2; these metrics increased to 97.5% and 91.2%, respectively, for PSA density 0.12ng/ml/ml. ISUP GG≥3 (Gleason ≥4+3) was found in 2.4% (15/617) of men with MRI scores 1-2. They key limitations of this study are the heterogeneity and retrospective nature of the data.

Conclusions: Multiparametric MRI when used in real-world settings is able to rule out csPCa accurately, suggesting that about one-third of men might avoid an immediate biopsy. Men should be counselled about the risk of missing some significant cancers.

Patient Summary: Multiparametric magnetic resonance imaging (MRI) is a useful tool for ruling out prostate cancer, especially when combined with prostate-specific antigen density (PSAD). Previous results published from specialist centres can be reproduced at smaller institutions. However, patients and their clinicians must be aware that an early diagnosis of clinically significant prostate cancer could be missed in nearly 10% of patients by relying on MRI and PSAD alone.
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http://dx.doi.org/10.1016/j.euf.2020.09.012DOI Listing
October 2020

RUNX1 marks a luminal castration-resistant lineage established at the onset of prostate development.

Elife 2020 10 7;9. Epub 2020 Oct 7.

Cancer Research United Kingdom, Stem Cell Biology Group, Cancer Research United Kingdom Manchester Institute, The University of Manchester, Alderley Park, Alderley Edge, Macclesfield, United Kingdom.

The characterization of prostate epithelial hierarchy and lineage heterogeneity is critical to understand its regenerative properties and malignancies. Here, we report that the transcription factor RUNX1 marks a specific subpopulation of proximal luminal cells (PLCs), enriched in the periurethral region of the developing and adult mouse prostate, and distinct from the previously identified NKX3.1 luminal castration-resistant cells. Using scRNA-seq profiling and genetic lineage tracing, we show that RUNX1 PLCs are unaffected by androgen deprivation, and do not contribute to the regeneration of the distal luminal compartments. Furthermore, we demonstrate that a transcriptionally similar RUNX1 population emerges at the onset of embryonic prostate specification to populate the proximal region of the ducts. Collectively, our results reveal that RUNX1 PLCs is an intrinsic castration-resistant and self-sustained lineage that emerges early during prostate development and provide new insights into the lineage relationships of the prostate epithelium.
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http://dx.doi.org/10.7554/eLife.60225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644213PMC
October 2020

UM171-Expanded Cord Blood Transplants Support Robust T Cell Reconstitution with Low Rates of Severe Infections.

Transplant Cell Ther 2021 Jan 3;27(1):76.e1-76.e9. Epub 2020 Oct 3.

Centre de recherche de l'Hôpital Maisonneuve-Rosemont, Montreal, Quebec, Canada; Department of Medicine, Université de Montréal, Montreal, Quebec, Canada; Division of Hematology-Oncology, Hôpital Maisonneuve-Rosemont, Montreal, Quebec, Canada. Electronic address:

Rapid T cell reconstitution following hematopoietic stem cell transplantation (HSCT) is essential for protection against infections and has been associated with lower incidence of chronic graft-versus-host disease (cGVHD), relapse, and transplant-related mortality (TRM). While cord blood (CB) transplants are associated with lower rates of cGVHD and relapse, their low stem cell content results in slower immune reconstitution and higher risk of graft failure, severe infections, and TRM. Recently, results of a phase I/II trial revealed that single UM171-expanded CB transplant allowed the use of smaller CB units without compromising engraftment (www.clinicaltrials.gov, NCT02668315). We assessed T cell reconstitution in patients who underwent transplantation with UM171-expanded CB grafts and retrospectively compared it to that of patients receiving unmanipulated CB transplants. While median T cell dose infused was at least 2 to 3 times lower than that of unmanipulated CB, numbers and phenotype of T cells at 3, 6, and 12 months post-transplant were similar between the 2 cohorts. T cell receptor sequencing analyses revealed that UM171 patients had greater T cell diversity and higher numbers of clonotypes at 12 months post-transplant. This was associated with higher counts of naive T cells and recent thymic emigrants, suggesting active thymopoiesis and correlating with the demonstration that UM171 expands common lymphoid progenitors in vitro. UM171 patients also showed rapid virus-specific T cell reactivity and significantly reduced incidence of severe infections. These results suggest that UM171 patients benefit from rapid T cell reconstitution, which likely contributes to the absence of moderate/severe cGVHD, infection-related mortality, and late TRM observed in this cohort.
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http://dx.doi.org/10.1016/j.bbmt.2020.09.031DOI Listing
January 2021

Newly diagnosed multiple myeloma patients treated with tandem auto-allogeneic stem cell transplant have better overall survival with similar outcomes at time of relapse compared to patients who received autologous transplant only.

Clin Transplant 2020 12 22;34(12):e14099. Epub 2020 Oct 22.

Division of Hematology, Oncology and Transplantation, Hôpital Maisonneuve-Rosemont and Université de Montréal, Montréal, QC, Canada.

Background: Long-term survival in patients progressing after tandem autologous-allogeneic stem cell transplant (SCT) has been reported, suggesting a persistent graft-vs-myeloma (GvM) effect even after post-transplant progression.

Methods: In order to confirm this observation, we updated the results of our previously published cohort of 92 newly diagnosed myeloma patients who received tandem transplant and compared them with 81 contemporary patients who received autologous transplant only.

Results: With a median follow-up of 13.1 and 10.2 years, respectively, median overall survival (OS) in the tandem group has not been reached, compared with 6.1 years after auto-SCT (P ≤ .001). Disease progression occurred less frequently after tandem transplant, with an estimated 10-year cumulative incidence of 49% vs 76% (P ≤ .001). Cumulative incidence of extensive chronic graft-vs-host disease (cGVHD) was high at 83%, with modest benefits on OS (60% vs 49%, P = .550) but sharp improvement of progression-free survival (PFS; 55% vs 10%, P = .002) at 10 years associated with development of cGVHD. After first progression, median OS was 5.8 years in tandem and 5.2 years in the auto-group (P = .062); median PFS was also similar.

Conclusion: Despite confirmation of better outcomes after upfront tandem transplant, our data do not support persistence of a strong, clinically significant graft-vs-myeloma effect after first progression, emphasizing the need to better characterize the GvM effect.
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http://dx.doi.org/10.1111/ctr.14099DOI Listing
December 2020

Perioral pressure ulcers in patients with COVID-19 requiring invasive mechanical ventilation.

Eur J Plast Surg 2020 Sep 15:1-6. Epub 2020 Sep 15.

Department of Plastic Surgery, Guy's & St. Thomas' Hospital, London, UK.

Background: Facial pressure ulcers are a rare yet significant complication. National Institute for Health and Care Excellence (NICE) guidelines recommend that patients should be risk-assessed for pressure ulcers and measures instated to prevent such complication. In this study, we report case series of perioral pressure ulcers developed following the use of two devices to secure endotracheal tubes in COVID-19 positive patients managed in the intensive care setting.

Methods: A retrospective analysis was conducted on sixteen patients identified to have perioral pressure ulcers by using the institutional risk management system. Data parameters included patient demographics (age, gender, comorbidities, smoking history and body mass index (BMI)). Data collection included the indication of admission to ITU, duration of intubation, types of medical devices utilised to secure the endotracheal tube, requirement of vasopressor agents and renal replacement therapy, presence of other associated ulcers, duration of proning and mortality.

Results: Sixteen patients developed different patterns of perioral pressure ulcers related to the use of two medical devices (Insight, AnchorFast). The mean age was 58.6 years. The average length of intubation was 18.8 days. Fourteen patients required proning, with an average duration of 5.2 days.

Conclusions: The two devices utilised to secure endotracheal tubes are associated with unique patterns of facial pressure ulcers. Measures should be taken to assess the skin regularly and avoid utilising devices that are associated with a high risk of facial pressure ulcers. Awareness and training should be provided to prevent such significant complication.Level of evidence: Level IV, risk/prognostic study.
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http://dx.doi.org/10.1007/s00238-020-01737-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490473PMC
September 2020

Targeting the BAF complex in advanced prostate cancer.

Expert Opin Drug Discov 2021 Feb 16;16(2):173-181. Epub 2020 Sep 16.

Urology Research Group, CRUK Beatson Institute , Glasgow, UK.

Introduction: The BRG1/BRM associated factors (BAF) complex is a chromatin remodeling SWI/SNF which is mutated in 20% of cancers. This complex has many interchangeable subunits which may have oncogenic or tumor suppressor activity in a context-dependent manner. The BAF complex is mutated in 35-50% of metastatic prostate cancer (PC); however, its role in advanced disease is unclear. This review attempts to consolidate current knowledge of the BAF complex in PC and explore potential therapeutic approaches.

Areas Covered: This review covers the known roles of some BAF subunits, their alterations, and the models which best explain their mechanisms in driving PC. Following this, the authors provide their expert perspective on how this complex could be targeted in the future with a personalized medicine approach.

Expert Opinion: Personalized medicine would allow for patient stratification to exploit synthetic lethal strategies in targeting a mutated BAF complex as shown experimentally in other cancers. BAF dependency can also be targeted in patients stratified for other molecular markers such as BRG1 targeting in phosphatase and tensin homolog (PTEN) deficient PC.
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http://dx.doi.org/10.1080/17460441.2020.1821644DOI Listing
February 2021

A prospective, observational, cohort study of airway management of patients with COVID-19 by specialist tracheal intubation teams.

Can J Anaesth 2021 02 4;68(2):196-203. Epub 2020 Sep 4.

Department of Anaesthesia, Guy's and St Thomas', NHS Foundation Trust, Great Maze Pond, London, SE1 9RT, UK.

Purpose: Because of the anticipated surge in cases requiring intensive care unit admission, the high aerosol-generating risk of tracheal intubation, and the specific requirements in coronavirus disease (COVID-19) patients, a dedicated Mobile Endotracheal Rapid Intubation Team (MERIT) was formed to ensure that a highly skilled team would be deployed to manage the airways of this cohort of patients. Here, we report our intubation team experience and activity as well as patient outcomes during the COVID-19 pandemic.

Methods: The MERIT members followed a protocolized early tracheal intubation model. Over a seven-week period during the peak of the pandemic, prospective data were collected on MERIT activity, COVID-19 symptoms or diagnosis in the team members, and demographic, procedural, and clinical outcomes of patients.

Results: We analyzed data from 150 primary tracheal intubation episodes, with 101 (67.3%) of those occurring in men, and with a mean (standard deviation) age of 55.7 (13.8) yr. Black, Asian, and minority ethnic groups accounted for 55.7% of patients. 91.3% of tracheal intubations were performed with videolaryngoscopy, and the first pass success rate was 88.0%. The 30-day survival was 69.2%, and the median [interquartile range] length of critical care stay was 11 [6-20] days and of hospital stay was 12 [7-22] days. Seven (11.1%) MERIT healthcare professionals self-isolated because of COVID-19 symptoms, with a total 41 days of clinical work lost. There was one reported incident of a breach of personal protective equipment and multiple anecdotal reports of doffing breaches.

Conclusion: We have shown that a highly skilled designated intubation team, following a protocolized, early tracheal intubation model may be beneficial in improving patient and staff safety, and could be considered by other institutions in future pandemic surges.
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http://dx.doi.org/10.1007/s12630-020-01804-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472940PMC
February 2021

Single-session, dual-site robotic surgery for synchronous primary malignancies of the oropharynx and thorax.

J Surg Case Rep 2020 Aug 26;2020(8):rjaa258. Epub 2020 Aug 26.

Department of Otorhinolaryngology Head and Neck Surgery, Guy's and St Thomas' NHS Foundation Trust, London, UK.

Single-session, dual-site robotic surgery for synchronous malignancies is not widely reported. To our knowledge, there are no previous reports of transoral robotic surgery (TORS) and robot-assisted thoracic surgery (RATS) in a single sitting. A 49-year-old male presented with a neck lump. Biopsies and imaging proved synchronous primaries of the tonsil and lung. The morbidity of primary dual-site chemoradiotherapy, or open surgery, presented a management challenge. We therefore opted for sequential robotic resections, in a single sitting. The patient was discharged on Day 6 post-operatively and was able to start radiotherapy less than 3 weeks post-operatively. Undertaking TORS and RATS in a single sitting is feasible and safe. This approach allowed fast-tracking of adjuvant oncological therapy, arguably conveying the greatest chance of cure. We detail the rationale and utility of this novel approach and describe the surgical and anaesthetic challenges of two teams undertaking sequential robotic procedures in a single sitting.
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http://dx.doi.org/10.1093/jscr/rjaa258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449555PMC
August 2020

HSV-1 Cytoplasmic Envelopment and Egress.

Int J Mol Sci 2020 Aug 19;21(17). Epub 2020 Aug 19.

Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.

Herpes simplex virus type 1 (HSV-1) is a structurally complex enveloped dsDNA virus that has evolved to replicate in human neurons and epithelia. Viral gene expression, DNA replication, capsid assembly, and genome packaging take place in the infected cell nucleus, which mature nucleocapsids exit by envelopment at the inner nuclear membrane then de-envelopment into the cytoplasm. Once in the cytoplasm, capsids travel along microtubules to reach, dock, and envelope at cytoplasmic organelles. This generates mature infectious HSV-1 particles that must then be sorted to the termini of sensory neurons, or to epithelial cell junctions, for spread to uninfected cells. The focus of this review is upon our current understanding of the viral and cellular molecular machinery that enables HSV-1 to travel within infected cells during egress and to manipulate cellular organelles to construct its envelope.
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http://dx.doi.org/10.3390/ijms21175969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503644PMC
August 2020

Efficacy and safety of nanosomal docetaxel lipid suspension based chemotherapy in gastric and gastroesophageal junction adenocarcinoma.

Mol Clin Oncol 2020 Sep 6;13(3):14. Epub 2020 Jul 6.

Jina Pharmaceuticals Inc., Libertyville, IL 60048, USA.

The current retrospective multicenter study evaluated the efficacy and safety of nanosomal docetaxel lipid suspension (NDLS; DoceAqualip) based chemotherapy in patients with gastric and gastroesophageal junction (GEJ) adenocarcinoma. The medical charts of patients with gastric and GEJ adenocarcinoma, who were treated with NDLS (50-75 mg/m; 3 weekly cycles) based chemotherapy and followed-up from April 2014 to September 2018, were analyzed. The study endpoints included overall response rate (ORR) and disease control rate (DCR) in neoadjuvant and metastatic settings. Overall survival (OS) and safety were also evaluated. Of the 43 patients with gastric (n=39) and GEJ (n=4) adenocarcinoma, efficacy evaluation was available in 35 (neoadjuvant, 17/18 patients; metastatic, 18/25 patients). In the neoadjuvant setting, an ORR of 58.82% and a DCR of 94.11% were observed, whereas in the metastatic setting, the ORR was 77.77% and the DCR was 83.33%. In the neoadjuvant setting, at a follow-up ranging from 0.7 to 41.2 months, the median OS was not reached. In the metastatic setting, the median OS was 31.9 months at a follow-up ranging from 0.2 to 50.3 months. At least one adverse event (AE) was reported in 24 patients. Anemia, lymphopenia and thrombocytopenia were the most common hematological AEs, while nausea, vomiting and weakness were the most common non-hematological AEs. NDLS based treatment was well-tolerated without any new safety concerns. Overall, NDLS-based chemotherapy was effective and well-tolerated in the management of gastric and GEJ adenocarcinoma.
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http://dx.doi.org/10.3892/mco.2020.2084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391841PMC
September 2020

Single UM171-expanded cord blood transplant can cure severe idiopathic aplastic anemia in absence of suitable donors.

Eur J Haematol 2020 Dec 31;105(6):808-811. Epub 2020 Aug 31.

Division of Hematology, Oncology and Transplantation, Hôpital Maisonneuve-Rosemont and Université de Montréal, Montréal, Québec, Canada.

Haplo-identical donors have been increasingly used as an alternative source of stem cells in patients with severe aplastic anemia in need of an allogeneic transplantation but lack a matched donor. Single cord blood (CB) transplant also offers a curative option for this disease, but few adult patients have been reported due to low number of progenitor cells leading to prolonged cytopenias and a high risk of infections. CB stem cell expansion may theoretically solve these pitfalls but has not been used previously in non-malignant diseases, likely due to fear of graft rejection and lack of availability of expanded CBs outside clinical trials. We report the first case of an adult patient with severe aplastic anemia who was successfully transplanted with a UM171-expanded CB graft. After a conditioning of rabbit antithymocyte globulin, fludarabine, cyclophosphamide, and total body irradiation, a UM171 expanded graft of 3.29 × 10 CD34 + cells/kg (a 51-fold increase) was infused. Full donor chimerism was observed on day + 14, with neutrophil and platelet engraftment on days + 23 and + 27. There was no severe infection or graft-vs-host disease. UM171-expanded grafts offer a valuable option for patients with aplastic anemia in need of transplantation but have no suitable donor.
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http://dx.doi.org/10.1111/ejh.13504DOI Listing
December 2020