Exploring the role of histone deacetylase inhibitors in cancer development and therapeutic potential.

The process of acetylation and deacetylation of histones within the nucleus operates within a dynamic equilibrium. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) collaboratively and precisely regulate normal gene transcription and expression. Any disorder in the activity of HATs/HDACs can lead to uncontrolled gene expression, consequently resulting in tumorigenesis. Histone deacetylase inhibitors (HDACIs) have the capacity to block the cell cycle, thereby restraining tumor cell proliferation and tumor growth. Also, HDACIs exhibit a significant capability to diminish the expression of apoptosis protein inhibitors such as Bcl-2 and B-cell lymphoma-extra-large (Bcl-xL), while concurrently up-regulating pro-apoptotic proteins such as Bax, Bad, and Bim. Also, HDACIs demonstrate the ability to inhibit tumor cell angiogenesis. Representing a new category of targeted anti-cancer therapeutics, HDACIs possess the capability to restore the expression of tumor suppressor genes, induce apoptosis, and stimulate cell differentiation. Additionally, they exert anti-cancer effects through diverse pathways both in vivo and in vitro, thereby presenting promising prospects in tumor therapy. This review delves into the involvement of HDACs in cancer pathology and the therapeutic potential of HDACIs as emerging drugs in cancer treatment.

Improvement of palliative care for people with intellectual disabilities: A multi-site evaluation.

BACKGROUND: To improve the quality of palliative care, six evidence-based tools were implemented in 10 care services specialised in care for people with intellectual disabilities. Contextual differences were taken into account by using a participatory action research approach. METHOD: The RE-AIM framework (Reach, Effectiveness, Adoption, Implementation and Maintenance) structured the evaluation. Data sources were online questionnaires completed by 299 professionals at baseline (response 45.2%) and 250 professionals after 2.5 years (35.1%), 11 semi-structured group interviews with 43 professionals, field notes and implementation plans. RESULTS: A total of 767 professionals and 43 teams were reached. The effectiveness of the intervention was demonstrated in an improved knowledge of palliative care policy and increased competences among professionals. 79% of the professionals adopted tools in the toolbox. The participatory action research method was perceived as valuable in driving change. CONCLUSIONS: Improving palliative care needs a context-specific, flexible approach, with involvement of all stakeholders.

Posterior open wound healing in immediate implant placement using reactive soft tissue versus absorbable collagen sponge: a retrospective cohort study.

The soft and hard tissue healing of open wounds in immediate implant placement are yet to be explored. The aim of this study was to compare the clinical outcomes of open wound healing using reactive soft tissue (RST) and absorbable collagen sponge (ACS). Forty implants placed immediately in posterior sockets were included; autologous RST was used in 20 and ACS substitute was used in 20. Soft tissue healing was primarily assessed through a novel scoring system and the evaluation of gingival recession. The horizontal bone width (HBW) and interproximal marginal bone level (MBL) were measured on radiographs to observe the hard tissue healing. No significant difference in total soft tissue healing score was observed at 2 weeks postoperatively. Notably, the ACS group showed better tissue colour (P = 0.016) but worse fibrous repair (P = 0.043) scores than the RST group. Gingival recession levels were comparable in the two groups, both before tooth extraction and after placement of the restoration. Regarding hard tissue, HBW and MBL changes showed no intergroup differences. Within the limitations of this study, both RST and ACS seemed effective for open wound closure, achieving ideal soft and hard tissue healing in immediate implant placement.

Genetic variants in African-American and Hispanic patients with breast cancer.

Breast cancer is a disease with significant health disparity affecting mortality in minority women. The present study examined the genetic makeup of breast cancers in African-American and Hispanic/Latinx patients to determine specific genetic mutations associated with breast cancer in the minority population from South Los Angeles, United States. Whole-exome sequencing was performed on DNA extracted from breast cancer tumor biopsies collected from 13 African-American and 15 Hispanic women and 8 matched-normal samples for each ethnic category. The results were analyzed using Ensemble Variant Effect Predictor and Mutation Significance. Additionally, a comparative analysis with The Cancer Genome Atlas data was provided. Our data revealed somatic mutations in genes such as SET domain containing (lysine methyltransferase) 8, serine protease 1 and AT-rich interaction domain 1B (ARID1B) and known breast cancer genes, such as BRCA1/2, TP53 and the DNA damage response genes across all ethnicities. Additionally, Hispanic patients had BRCA1 associated RING domain 1B (BARD1) variants, while African-American patients had higher numbers of nonsynonymous variants in the RAD51 paralog B (RAD51B), ARID1B and X-ray repair cross complementing 3 (XRCC3) genes. In addition, our patients exhibited mutational signature enrichment that indicated DNA homologous recombination repair deficiencies. Therefore, African-American and Hispanic breast cancer samples showed considerable overlap in breast cancer genetic mutations. However, there are differences in specific genetic variants in TP53, BRCA1/2, BARD1 or ARID1B, which will require further study of their role in tumorigenesis.

Autoantibody and T cell responses to oxidative post-translationally modified insulin neoantigenic peptides in type 1 diabetes.

AIMS/HYPOTHESIS: Antibodies specific to oxidative post-translational modifications (oxPTM) of insulin (oxPTM-INS) are present in most individuals with type 1 diabetes, even before the clinical onset. However, the antigenic determinants of such response are still unknown. In this study, we investigated the antibody response to oxPTM-INS neoepitope peptides (oxPTM-INSPs) and evaluated their ability to stimulate humoral and T cell responses in type 1 diabetes. We also assessed the concordance between antibody and T cell responses to the oxPTM-INS neoantigenic peptides. METHODS: oxPTM-INS was generated by exposing insulin to various reactive oxidants. The insulin fragments resulting from oxPTM were fractionated by size-exclusion chromatography further to ELISA and LC-MS/MS analysis to identify the oxidised peptide neoepitopes. Immunogenic peptide candidates were produced and then modified in house or designed to incorporate in silico-oxidised amino acids during synthesis. Autoantibodies to the oxPTM-INSPs were tested by ELISA using sera from 63 participants with new-onset type 1 diabetes and 30 control participants. An additional 18 fresh blood samples from participants with recently diagnosed type 1 diabetes, five with established disease, and from 11 control participants were used to evaluate, in parallel, CD4+ and CD8+ T cell activation by oxPTM-INSPs. RESULTS: We observed antibody and T cell responses to three out of six LC-MS/MS-identified insulin peptide candidates: A:12-21 (SLYQLENYCN, native insulin peptide 3 [Nt-INSP-3]), B:11-30 (LVEALYLVCGERGFFYTPKT, Nt-INSP-4) and B:21-30 (ERGFFYTPKT, Nt-INSP-6). For Nt-INSP-4 and Nt-INSP-6, serum antibody binding was stronger in type 1 diabetes compared with healthy control participants (p≤0.02), with oxidised forms of ERGFFYTPKT, oxPTM-INSP-6 conferring the highest antibody binding (83% binders to peptide modified in house by hydroxyl radical [●OH] and >88% to in silico-oxidised peptide; p≤0.001 vs control participants). Nt-INSP-4 induced the strongest T cell stimulation in type 1 diabetes compared with control participants for both CD4+ (p<0.001) and CD8+ (p=0.049). CD4+ response to oxPTM-INSP-6 was also commoner in type 1 diabetes than in control participants (66.7% vs 27.3%; p=0.039). Among individuals with type 1 diabetes, the CD4+ response to oxPTM-INSP-6 was more frequent than to Nt-INSP-6 (66.7% vs 27.8%; p=0.045). Overall, 44.4% of patients showed a concordant autoimmune response to oxPTM-INSP involving simultaneously CD4+ and CD8+ T cells and autoantibodies. CONCLUSIONS/INTERPRETATION: Our findings support the concept that oxidative stress, and neoantigenic epitopes of insulin, may be involved in the immunopathogenesis of type 1 diabetes.

Use of reactive soft tissue for primary wound closure during immediate implant placement: a two-year retrospective study.

Sockets with both hard and soft tissue defects present a challenge for immediate implant placement. A modified technique harnessing the reactive soft tissue in the extraction socket for primary closure has been reported to contribute to hard and soft tissue augmentation after immediate implantation. The aim of this study was to evaluate the effects of this novel technique on the hard and soft tissues of sockets with both buccal bone and soft tissue defects (group B) and to compare the outcomes with those obtained for sockets with intact soft tissue but buccal bone dehiscence (group A). Thirty-two implants placed in the posterior region were included: 17 in group A, 15 in group B. The implants were inserted immediately utilizing reactive soft tissue from the socket for primary closure in both groups. The changes in buccal bone dimensions after 6 months were generally comparable between the two groups. A keratinized mucosa reduction of 0.56 mm in group A and keratinized mucosa gain of 0.67 mm in group B were observed at 6 months (P = 0.009). The bone and soft tissue levels were well maintained in both groups after 2 years. This technique may be a potential treatment method for tissue augmentation during immediate implantation in posterior sockets, even when a buccal bony defect and mucogingival recession need to be repaired at the same time.

Relationship between objective and subjective hydration measures on sprint performance among soccer players during actual matches in hot and humid environment.

BACKGROUND: Studies that investigate the effect of hydration on soccer performance in the heat are mostly carried out in a laboratory-controlled environment or simulated setting. Generally, on site, hydration is measured subjectively. Hence, the relationships between objective and subjective hydration measures during actual soccer matches in natural hot and humid environment with performance remain unclear. METHODS: Forty-two soccer players (age: 27.34±3.62 years; BMI: 23.80±2.70 kg/m2; temperature: 30.8±1.92 °C; humidity: 82±1.4%) hydration status were assessed using urine specific gravity (USG) and bodyweight (BW) as the objective measures, meanwhile, thirst was measured subjectively using a thirst scale. For performance evaluation, 20 and 50 m sprint time were measured before and after match. RESULTS: The results showed a significant relationship between USG and sprint time (r=1.00, CI 0.98-0.99; P<0.05), and as expected, USG at post-match was significantly higher than pre-match (P<0.05) indicating dehydration. In line, changes (between post and pre-match) in BW also showed positive relationship with changes in sprint time (r=0.99, CI 0.98-0.99; P<0.05). Not to our expectation, the self-reported thirst level was not found to be correlated with USG and sprint time. CONCLUSIONS: Objective measures better reflect hydration status and predict sprint performance compared to subjective measure when playing in hot and humid environment. Players need to monitor their hydration status to maintain their sprint performances.

[Application of face scanning in implant-supported restoration treatment of dentition defect].

In recent years, the increasingly mature oral digital technology has opened a new era of implant treatment. Before implant treatment, digital information is collected from various aspects and virtual patients are constructed based on three-dimensional (3D) scanning technology, and this greatly optimizes the preoperative virtual tooth arrangement, esthetic design and implant treatment plan, and brings great clinical convenience to patients and doctors. In this review, the application and new progress of facial 3D scanning technology in the field of implantology will be described, and the opportunities and challenges brought by digitalization technology to clinicians will be deeply discussed, in order to provide a reference for implantologists to fully understand the application of digitalization in the field of implantology.

Coating an adenovirus with functionalized gold nanoparticles favors uptake, intracellular trafficking and anti-cancer therapeutic efficacy.

Adenoviral (Ad) vectors have proven to be important tools for gene and cell therapy, although some issues still need to be addressed, such as undesired interactions with blood components and off-target sequestration that ultimately hamper efficacy. In the past years, several organic and inorganic materials have been developed to reduce immunogenicity and improve biodistribution of Ad vectors. Here we investigated the influence of the functionalization of 14 nm PEGylated gold nanoparticles (AuNPs) with quaternary ammonium groups and an arginine-glycine-aspartic acid (RGD)-motif on the uptake and biodistribution of Ad vectors. We report the formation of Ad@AuNPs complexes that promote cell attachment and uptake, independently of the presence of the coxsackievirus and adenovirus receptor (CAR) and αvß3 and αvß5 integrins, significantly improving transduction without limiting Ad bioactivity. Besides, the presence of the RGD peptide favors tumor targeting and decreases Ad sequestration in the liver. Additionally, tumor delivery of a coated Ad vector expressing the human sodium iodide symporter (hNIS) by mesenchymal stem cells induces increased accumulation of radioactive iodine (131I) and tumor volume reduction compared to naked Ad-hNIS, highlighting the promising potential of our coating formulation in cancer gene therapy. STATEMENT OF SIGNIFICANCE: Modification of adenoviral vectors with lipids and polymers can reduce interactions with blood components and increase tumor accumulation; however, increased toxicity and reduced transduction efficiency were indicated. Coating with gold nanoparticles has proven to be a successful strategy for increasing the efficiency of transduction of receptor-defective cell lines. Here we explore the contribution of cell surface receptors on the mechanisms of entry of Ad vectors coated with gold nanoparticles in cell lines with varying degrees of resistance to infection. The enhancement of the anti-tumoral effect shown in this work provides new evidence for the potential of our formulation.

Blood Flow Velocimetry in a Microchannel During Coagulation Using Particle Image Velocimetry and Wavelet-Based Optical Flow Velocimetry.

This article describes novel measurements of the velocity of whole blood flow in a microchannel during coagulation. The blood is imaged volumetrically using a simple optical setup involving a white light source and a microscope camera. The images are processed using particle image velocimetry (PIV) and wavelet-based optical flow velocimetry (wOFV), both of which use images of individual blood cells as flow tracers. Measurements of several clinically relevant parameters such as the clotting time, decay rate, and blockage ratio are computed. The high-resolution wOFV results yield highly detailed information regarding thrombus formation and corresponding flow evolution that is the first of its kind.

Hypoxia and its therapeutic possibilities in paediatric cancers.

In tumours, hypoxia-a condition in which the demand for oxygen is higher than its availability-is well known to be associated with reduced sensitivity to radiotherapy and chemotherapy, and with immunosuppression. The consequences of hypoxia on tumour biology and patient outcomes have therefore led to the investigation of strategies that can alleviate hypoxia in cancer cells, with the aim of sensitising cells to treatments. An alternative therapeutic approach involves the design of prodrugs that are activated by hypoxic cells. Increasing evidence indicates that hypoxia is not just clinically significant in adult cancers but also in paediatric cancers. We evaluate relevant methods to assess the levels and extent of hypoxia in childhood cancers, including novel imaging strategies such as oxygen-enhanced magnetic resonance imaging (MRI). Preclinical and clinical evidence largely supports the use of hypoxia-targeting drugs in children, and we describe the critical need to identify robust predictive biomarkers for the use of such drugs in future paediatric clinical trials. Ultimately, a more personalised approach to treatment that includes targeting hypoxic tumour cells might improve outcomes in subgroups of paediatric cancer patients.

Neural peptide promotes the angiogenesis and osteogenesis around oral implants.

Generally, impaired bones heal by bone repair and bone regeneration. These two processes are necessary during the healing period of dental implant. Vasculature plays a crucial role in bone healing because bones are highly vascularized tissue. Osteogenesis and angiogenesis are highly coupled processes and can be regulated by Hippo-YAP signaling pathway. Recent studies have demonstrated Hippo-YAP pathway may be regulated by alpha calcitonin gene-related peptide. However, the regulatory effects of αCGRP-YAP pathway on angiogenesis and osteogenesis during bone healing around implants remain unclear. Four groups of mice were established: KO Group: αCGRP -/- mice; KO + αCGRP group: αCGRP -/- mice with αCGRP overexpressing lentiviral transfection; KO + YAP group: αCGRP -/- mice with YAP overexpressing lentiviral transfection; WT group: wildtype mice. After 14 or 28 days, animals were sacrificed and tested. Results showed αCGRP deficiency hampered osteogenesis and angiogenesis. In addition, the impaired bone healing can be rescued by overexpressing αCGRP and YAP in αCGRP -/- mice. In-vivo results indicate αCGRP-YAP pathway promotes angiogenesis and osteogenesis in bone healing, especially at the early stage. Taken together, present study demonstrated αCGRP up-regulate the expression of YAP, and down-stream genes to promote the osteogenesis and angiogenesis around the implants.

The effect of head positioning on cerebral hemodynamics: Experiences in mild ischemic stroke.

BACKGROUND AND PURPOSE: It is generally agreed that optimal head positioning is an important consideration in acute stroke management regime. However, there is limited literature investigating the effect of head positioning changes on cerebrovascular physiology in acute ischemic stroke (AIS). We aim to assess cerebral autoregulation (CA) and associated hemodynamic responses during gradual head positioning (GHP) changes, between AIS and controls. METHODS: Cerebral blood flow velocity (CBFV, transcranial Doppler), blood pressure (BP, Finometer) and end-tidal CO2 (capnography) were recorded between lying flat (0°) and sitting up (30°) head position, in 16 controls (8 women, mean age 57 ± 16 yrs) and 15 AIS patients (7 women, 69 ± 8 yrs). AIS patients carried out three visits at 13.3 ± 6.9 h, 4.8 ± 3.2 days and 93.9 ± 11.5 days from symptom onset, respectively. RESULTS: AIS patients were significantly hypertensive (p = 0.005), hypocapnic (p < 0.001), and had lower CBFV (p = 0.02) compared to controls, in both head positions. When comparing 5-min FLAT to SIT head position, reductions in BP (both AIS and controls, p < 0.001) and CBFV (controls only: dominant hemisphere p = 0.001 and non-dominant hemisphere p = 0.05) were demonstrated. Of note, a reduction in autoregulation index was observed in AIS, after 5-min SIT head positioning, at all 3 visits (p = 0.018). CONCLUSION: Key hemodynamic changes were demonstrated when the head position changes from 5-min FLAT to SIT head position (GHP) in mildly affected stroke patients. Importantly, these were associated with non-significant changes in CBFV but reduced measures of CA following AIS, which may be relevant in determining the optimal head position and the ideal timing of mobilisation. Clinical Trial Registration - URL: http://www.clinicaltrials.gov. Unique Identifier: NCT02932540.

Cerebral hemodynamics in stroke thrombolysis (CHiST) study.

Despite careful patient selection, successful recanalization in intravenous thrombolysis is only achieved in approximately 50% of cases. Understanding changes in cerebral autoregulation during and following successful recanalization in acute ischemic stroke patients who receive intravenous thrombolysis, may inform the management of common physiological perturbations, including blood pressure, in turn reducing the risk of reperfusion injury. Cerebral blood velocity (Transcranial Doppler), blood pressure (Finometer) and end-tidal carbon dioxide (capnography) were continuously recorded in 11 acute ischemic stroke patients who received intravenous thrombolysis (5 female, mean ± SD age 68±12 years) over 4-time points, during and at the following time intervals after intravenous thrombolysis: 23.9±2.6 hrs, 18.1±7.0 days and 89.6±4.2 days. Reductions in blood pressure (p = 0.04) were observed during intravenous thrombolysis. Reductions in heart rate (p<0.005) and critical closing pressure [Affected hemisphere (p = 0.02) and non-affected hemisphere (p<0.005)] were observed post intravenous thrombolysis. End-tidal CO2 increased during the sub-acute and chronic stages (p = 0.028). Reduction in affected hemisphere phase at low frequency was observed during intravenous thrombolysis (p = 0.021) and at subsequent visits (p = 0.048). No changes were observed in cerebral blood velocity, coherence, gain and Autoregulation Index during the follow-up period. Intravenous thrombolysis in acute ischemic stroke patients induced changes in affected hemisphere phase and other key hemodynamic parameters, but not Autoregulation Index. Further investigation of cerebral autoregulation is warranted in a larger acute ischemic stroke cohort to inform its potential role in individualized management plans.

The Effects of Gradual Change in Head Positioning on the Relationship between Systemic and Cerebral Haemodynamic Parameters in Healthy Controls and Acute Ischaemic Stroke Patients.

(1) Background: Larger blood pressure variability (BPv) in the first 3 h post-stroke onset increases pathophysiological effects such as infarct size, and leads to greater risk of disability, comorbidities and mortality at 90 days. However, there is limited information on the relationship between systemic and cerebral haemodynamic and variability parameters. (2) Objectives: This study determined the effect of a gradual change in head position (GHP) on cerebral blood flow velocity variability (CBFVv) and mean arterial blood pressure variability (MABPv), in healthy controls and acute ischaemic stroke (AIS) patients. Methods: CBFVv and MABPv were expressed as standard deviation (SD) and coefficient of variation. A total of 16 healthy controls (mean age 57 ± 16 years) were assessed over two visits, 12 ± 8 days apart, and 15 AIS patients (mean age 69 ± 8.5 years) were assessed over three visits (V1: 13.3 ± 6.9 h, V2: 4.9 ± 3.2 days and V3: 93.9 ± 11.5 days post-stroke). (3) Results: In response to GHP, MABPv does not initially increase, but over time MABPv showed a significant increase in response to GHP in AIS (visits 2 and 3) and controls (visit 2). Additionally, in response to GHP in AIS, CBFVv increased in the affected hemisphere. Lastly, in AIS, a significant correlation between CBFVv and MABPv, assessed by SD, was seen in the unaffected hemisphere, whereas this relationship was not demonstrated in the affected hemisphere. (4) Conclusions: To our knowledge, this is the first study to analyse the relationship between CBFVv and MABPv. Shedding light on the effect of head position on the relationship between cerebral blood flow and blood pressure is important to improve our understanding of the underlying effects of cerebral autoregulation impairment. This early mechanistic study provides evidence supporting supine head positioning in healthy controls and stroke patients, through demonstration of a reduction of MABPv and increase in CBFVv.

Cerebral autoregulation and response to intravenous thrombolysis for acute ischemic stroke.

We hypothesized that knowledge of cerebral autoregulation (CA) status during recanalization therapies could guide further studies aimed at neuroprotection targeting penumbral tissue, especially in patients that do not respond to therapy. Thus, we assessed CA status of patients with acute ischemic stroke (AIS) during intravenous r-tPA therapy and associated CA with response to therapy. AIS patients eligible for intravenous r-tPA therapy were recruited. Cerebral blood flow velocities (transcranial Doppler) from middle cerebral artery and blood pressure (Finometer) were recorded to calculate the autoregulation index (ARI, as surrogate for CA). National Institute of Health Stroke Score was assessed and used to define responders to therapy (improvement of ≥ 4 points on NIHSS measured 24-48 h after therapy). CA was considered impaired if ARI < 4. In 38 patients studied, compared to responders, non-responders had significantly lower ARI values (affected hemisphere: 5.0 vs. 3.6; unaffected hemisphere: 5.4 vs. 4.4, p = 0.03) and more likely to have impaired CA (32% vs. 62%, p = 0.02) during thrombolysis. In conclusion, CA during thrombolysis was impaired in patients who did not respond to therapy. This variable should be investigated as a predictor of the response to therapy and to subsequent neurological outcome.

Gastrointestinal Manifestations of SARS-CoV-2 Infection and Virus Load in Fecal Samples From a Hong Kong Cohort: Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which has been characterized by fever, respiratory, and gastrointestinal symptoms as well as shedding of virus RNA into feces. We performed a systematic review and meta-analysis of published gastrointestinal symptoms and detection of virus in stool and also summarized data from a cohort of patients with COVID-19 in Hong Kong. METHODS: We collected data from the cohort of patients with COVID-19 in Hong Kong (N = 59; diagnosis from February 2 through February 29, 2020),and searched PubMed, Embase, Cochrane, and 3 Chinese databases through March 11, 2020, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We analyzed pooled data on the prevalence of overall and individual gastrointestinal symptoms (loss of appetite, nausea, vomiting, diarrhea, and abdominal pain or discomfort) using a random effects model. RESULTS: Among the 59 patients with COVID-19 in Hong Kong, 15 patients (25.4%) had gastrointestinal symptoms, and 9 patients (15.3%) had stool that tested positive for virus RNA. Stool viral RNA was detected in 38.5% and 8.7% among those with and without diarrhea, respectively (P = .02). The median fecal viral load was 5.1 log10 copies per milliliter in patients with diarrhea vs 3.9 log10 copies per milliliter in patients without diarrhea (P = .06). In a meta-analysis of 60 studies comprising 4243 patients, the pooled prevalence of all gastrointestinal symptoms was 17.6% (95% confidence interval [CI], 12.3-24.5); 11.8% of patients with nonsevere COVID-19 had gastrointestinal symptoms (95% CI, 4.1-29.1), and 17.1% of patients with severe COVID-19 had gastrointestinal symptoms (95% CI, 6.9-36.7). In the meta-analysis, the pooled prevalence of stool samples that were positive for virus RNA was 48.1% (95% CI, 38.3-57.9); of these samples, 70.3% of those collected after loss of virus from respiratory specimens tested positive for the virus (95% CI, 49.6-85.1). CONCLUSIONS: In an analysis of data from the Hong Kong cohort of patients with COVID-19 and a meta-analysis of findings from publications, we found that 17.6% of patients with COVID-19 had gastrointestinal symptoms. Virus RNA was detected in stool samples from 48.1% patients, even in stool collected after respiratory samples had negative test results. Health care workers should therefore exercise caution in collecting fecal samples or performing endoscopic procedures in patients with COVID-19, even during patient recovery.

Can we assess dynamic cerebral autoregulation in stroke patients with high rates of cardiac ectopicity?

It is unclear whether physiological recordings containing high numbers of ectopic heartbeats can be used to measure the cerebral autoregulation (CA) of blood flow. This study evaluated the utility of such data for assessing dynamic CA capacity. Physiological recordings of cerebral blood flow velocity, heart rate, end-tidal CO2 and beat-to-beat blood pressure from acute ischaemic stroke (AIS) patients (n = 46) containing ectopic heartbeats of varying number (0.2 to 25 occurrences per minute) were analysed. Dynamic CA was determined using the autoregulation index (ARI) and the normalised mean square error (NMSE) was used to evaluate the fitting of the step response between BP and CBFV to Tiecks' model. We fitted linear mixed models on the CA variables incorporating ectopic burden, age, sex and hemisphere as predictor variables. Ectopic activity demonstrated an association with mean coherence (p = 0.006) but not with ARI (p = 0.162), impaired CA based on dichotomised ARI (p = 0.859) or NMSE (p = 0.671). Dynamic CA could be reliably assessed in AIS patients using physiological recordings with high rates of cardiac ectopic activity. This provides supportive data for future studies evaluating CA capability in AIS patients, with the potential to develop more individualised treatment strategies. Graphical Abstract.

[Value of dual-energy CT-based volumetric iodine-uptake in the evaluation of chemotherapy efficacy in advanced gastric cancer].

Objective: To explore the value of dual-energy CT-based volumetric iodine-uptake (VIU) in the evaluation of chemotherapy efficacy in advanced gastric cancer. Methods: Inclusion criteria of subjects: (1) without previous systematic therapy; (2) with complete clinical information before and after chemotherapy; (3) without contraindications of chemotherapy. Exclusion criteria of subjects: (1) unfinished duration and times of chemotherapy; (2) unmeasurable primary lesions; (3) poor imaging quality or poor gastric filling. Clinical and image data of 52 patients with advanced gastric cancer who were diagnosed by pathology from gastroscopic biopsy, and needed chemotherapy evaluated by imaging and clinical information in the First Affiliated Hospital of Wenzhou Medical University from February 2017 to February 2018 were collected and analyzed. Of 52 patients, 38 were male and 14 were female with the median age of 65 (31-88) years old. All the patients underwent a dual-energy, dual phase-enhanced CT scanning before chemotherapy and after the third chemotherapy session. The parameters of the lesions measured before and after chemotherapy in portal vein phase were as follows: the maximum diameter (the largest diameter among those measured in the cross-sectional, coronal, and sagittal planes), average CT value (the regions of interest were manually pinpointed under cross-sectional planes with largest diameter of the tumor, which did not include regions less than 2 mm to the edge of the tumor) and VIU (lesion volume × iodine concentration). The change rates of maximum lesion diameter, average CT value and VIU before and after chemotherapy were calculated [(post-chemotherapy parameters-pre-chemotherapy parameters)/ pre-chemotherapy parameters]. The efficacy of chemotherapy was evaluated by RECIST 1.1 (the change of maximum tumor diameter after chemotherapy), Choi (the change of average CT value after chemotherapy) and VIU (the change of VIU after chemotherapy), respectively, which was categorized by complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Patients with CR, PR, and SD were assigned to the effective group, while those with PD were classified as the ineffective group. Paired t - test or Wilcoxon signed ranks test was used to compare the changes of parameters before and after chemotherapy, whereas Spearman correlation analysis and Kappa test were used for the correlation analysis and the consistency test between the three evaluation criteria (Kappa≥0.75 indicated good consistency). Results: After chemotherapy, the average CT value [(74.01±16.75) HU vs. (81.06±15.87) HU, t=2.202, P=0.030] and median VIU (668.53×10(2) µg vs. 272.52×10(2) µg, Z=4.761, P<0.001) decreased significantly, while the difference of the maximum diameter was not statistically significant [(66.71±34.49) mm vs. (78.45±35.62) mm, t=1.708, P=0.091]. The median change rate of VIU (-53.33%) was greater than that of CT values (-5.75%) with significant difference (Z=-5.408, P<0.001). According to the RECIST 1.1 criteria, 47 patients (90.4%, including 19 with PR and 28 with SD) were effective and 5 patients (9.6%) were ineffective. According to the Choi criteria, 45 patients (86.5%, including 37 with PR and 8 with SD) were effective and 7 patients (13.5%) were ineffective. According to the VIU criteria, 46 patients (88.5%, including 41 with PR and 5 with SD) were effective and 6 patients (11.5%) were ineffective. Efficacy comparison among these three criteria showed no significant difference (χ(2)=0.377, P=0.828). As compared to RECIST 1.1 evaluation, the proportion of PR evaluated by Choi and VIU was significantly higher (χ(2)=16.861, P<0.001), whereas the proportion of SD was significantly lower (χ(2)=24.089, P<0.001). There was no significant difference in the proportions of PR and SD between VIU and Choi criteria (χ(2)=0.887, P=0.346). Consistency and correlation analysis showed that the VIU and Choi evaluation criteria presented the highest consistency and correlation (Kappa=0.912, P<0.001; r=0.916, P<0.001). Conclusion: VIU is a feasible parameter for the evaluation of chemotherapy efficacy in advanced gastric cancer, and may be more sensitive than the evaluation criteria based on maximum diameter or change of CT value in the tumor.

Systemic delivery and SPECT/CT in vivo imaging of 125I-labelled oncolytic adenoviral mutants in models of pancreatic cancer.

Early phase clinical trials have demonstrated good therapeutic index for oncolytic adenoviruses in patients with solid tumours when administered intratumorally, resulting in local tumour elimination. Entrapment and binding of adenovirus to erythrocytes, blood factors, and neutralising antibodies have prevented efficient systemic delivery and targeting of distant lesions in the clinic. We previously generated the novel replication-selective Ad-3∆-A20T to improve tumour targeting by increasing the viral dose at distant sites. Here, we developed a protocol to directly radiolabel the virus for rapid and sensitive detection by single-photon emitted computed tomography (SPECT/CT) providing a convenient method for determining biodistribution following intravenous administration in murine models. Longitudinal whole-body scans, demonstrated efficient viral uptake in pancreatic Suit-2 and Panc04.03 xenografts with trace amounts of 125I-Ad-3∆-A20T up to 48 h after tail vein delivery. Hepatic and splenic radioactivity decreased over time. Analysis of tissues harvested at the end of the study, confirmed potency and selectivity of mutant viruses. Ad-3∆-A20T-treated animals showed higher viral genome copy numbers and E1A gene expression in tumors than in liver and spleen compared to Ad5wt. Our direct radiolabeling approach, allows for immediate screening of novel oncolytic adenoviruses and selection of optimal viral genome alterations to generate improved mutants.