Pancreatic cancer is a lethal disease with poor prognosis. Gemcitabine has been the first line systemic treatment for pancreatic cancer. However, the rapid development of drug resistance has been a ...major hurdle in gemcitabine therapy leading to unsatisfactory patient outcomes. With the recent renewed understanding of glutamine metabolism involvement in drug resistance and immuno-response, we investigated the anti-tumor effect of a glutamine analog (6-diazo-5-oxo-L-norleucine) as an adjuvant treatment to sensitize chemoresistant pancreatic cancer cells. We demonstrate that disruption of glutamine metabolic pathways improves the efficacy of gemcitabine treatment. Such a disruption induces a cascade of events which impacts glycan biosynthesis through Hexosamine Biosynthesis Pathway (HBP), as well as cellular redox homeostasis, resulting in global changes in protein glycosylation, expression and functional effects. The proteome alterations induced in the resistant cancer cells and the secreted exosomes are intricately associated with the reduction in cell proliferation and the enhancement of cancer cell chemosensitivity. Proteins associated with EGFR signaling, including downstream AKT-mTOR pathways, MAPK pathway, as well as redox enzymes were downregulated in response to disruption of glutamine metabolic pathways.
Summary
Background
Leishmania (Viannia) guyanensis is believed to be the principal cause of cutaneous leishmaniasis (CL) in Suriname. This disease is treated with pentamidine isethionate (PI), but ...treatment failure has increasingly been reported.
Aim
To evaluate PI for its clinical efficacy, to compare parasite load, and to assess the possibility of treatment failure due to other infecting Leishmania species.
Methods
Parasite load of patients with CL was determined in skin biopsies using real‐time quantitative PCR before treatment and 6 and 12 weeks after treatment. Clinical responses were evaluated at week 12 and compared with parasite load. In parallel, molecular species differentiation was performed.
Results
L. (V.) guyanensis was the main infecting species in 129 of 143 patients (about 90%). PI treatment led to a significant decrease (P < 0.001) in parasite counts, and cured about 75% of these patients. Treatment failure was attributable to infections with Leishmania (Viannia) braziliensis, Leishmania (Leishmania) amazonensis and L. (V.) guyanensis (1/92, 1/92 and 22/92 evaluable cases, respectively). There was substantial agreement beyond chance between the parasite load at week 6 and the clinical outcome at week 12, as indicated by the κ value of 0.61.
Conclusions
L. (V.) guyanensis is the main infecting species of CL in Suriname, followed by L. (V.) braziliensis and L. (L.) amazonensis. Furthermore, patient response to PI can be better anticipated based on the parasite load 6 weeks after the treatment rather than on parasite load before treatment.
Background
Pulmonary vein isolation (PVI) using radiofrequency catheter ablation is a widely accepted therapy for drug‐refractory atrial fibrillation patients. Elimination of the negative component ...of the local unipolar electrogram (UEGM) during PVI is a marker of transmural lesion formation. The ablation index (AI) can predict the quality of ablation lesion. Combining these two parameters could make PVI safer and efficient. The purpose of this pilot study was to examine the correlation between UEGM modification characteristics of the different target areas of left atrium and the associated AI values during PVI.
Methods
We analyzed 10 patients who underwent PVI using radiofrequency energy. The local electrophysiological properties and ablation parameters of 15 designated areas of interest in the left atria targeted by radiofrequency catheter ablation were collected.
Results
Out of the 10 patients, six were men (mean age 66 years) and 80% had paroxysmal AF. The mean time to achieve the UEGM modification in the posterior wall was shorter than that of the anterior wall (8.9 seconds vs. 11.1 s, respectively). The UEGM modification for every lesion was achieved at significantly lower AI values than conventional AIs (p < .001).
Conclusion
During PVI, the AIs deduced according to the local UEGM modification are markedly shorter than those generally recommended AIs in contemporary practice. This indicates that conventionally recommended AIs could be safely reduced while ensuring the efficacy and quality of radiofrequency ablation during PVI. This approach would probably reduce to risk of collateral thermal injuries.
We conducted a systematic review examining the cost effectiveness of a 3-month course of isoniazid and rifapentine, known as 3HP, given by directly observed treatment, compared to 9 months of ...isoniazid that is directly observed or self-administered, for latent tuberculosis infection. 3HP has shown to be effective in reducing progression to active tuberculosis and like other short-course regimens, has higher treatment completion rates compared to standard regimens such as 9 months of isoniazid. Decision makers would benefit from knowing if the higher up-front costs of rifapentine and of the human resources needed for directly observed treatment are worth the investment for improved outcomes.
We searched PubMed, Embase, CINAHL, LILACS, and Web of Science up to February 2022 with search concepts combining latent tuberculosis infection, directly observed treatment, and cost or cost-effectiveness. Studies included were in English or French, on human subjects, with latent tuberculosis infection, provided information on specified anti-tubercular therapy regimens, had a directly observed treatment arm, and described outcomes with some cost or economic data. We excluded posters and abstracts, treatment for multiple drug resistant tuberculosis, and combined testing and treatment strategies. We then restricted our findings to studies examining directly-observed 3HP for comparison. The primary outcome was the cost and cost-effectiveness of directly-observed 3HP.
We identified 3 costing studies and 7 cost-effectiveness studies. The 3 costing studies compared directly-observed 3HP to directly-observed 9 months of isoniazid. Of the 7 cost-effectiveness studies, 4 were modelling studies based in high-income countries; one study was modelled on a high tuberculosis incidence population in the Canadian Arctic, using empiric costing data from that setting; and 2 studies were conducted in a low-income, high HIV-coinfection rate population. In five studies, directly-observed 3HP compared to self-administered isoniazid for 9 months in high-income countries, has incremental cost-effectiveness ratios that range from cost-saving to $5418 USD/QALY gained. While limited, existing evidence suggests 3HP may not be cost-effective in low-income, high HIV-coinfection settings.
Cost-effectiveness should continue to be assessed for programmatic planning and scale-up, and may vary depending on existing systems and local context, including prevalence rates and patient expectations and preferences.
Patients with extensive ulcerative colitis(UC) of more than eight years duration have an increased risk of colorectal cancer. Molecular biomarkers for dysplasia and cancer could have a great clinical ...value in managing cancer risk in these UC patients. Using a wide range of molecular techniques- including cutting-edge OMICS technologies- recent studies have identified clinically relevant biomarker candidates from a variety of biosamples, including colonic biopsies, blood, stool, and urine. While the challenge remains to validate these candidate biomarkers in multi-center studies and with larger patient cohorts, it is certain that accurate biomarkers of colitis-associated neoplasia would improve clinical management of neoplastic risk in UC patients. This review highlights the ongoing avenues of research in biomarker development for colitis-associated colorectal cancer.
Facemasks are widely used as a protective measure by general public to prevent inhalation of airborne pathogens including seasonal, swine and other forms of influenza and severe acute respiratory ...syndrome (SARS), etc. However, scientific data on effectiveness of facemasks in reducing infections in the community are extremely limited and even inconsistent. In this work, two manikins labelled as ‘source’ and ‘susceptible’ were used to measure the protection provided by facemasks under various emission scenarios. The source was modified to generate polydisperse ultrafine particles, whereas the susceptible was modified to mimic a realistic breathing pattern. The facemask was challenged by both pseudo-steady and highly transient emissions generated by an expiratory process where parameters, such as separation distance between manikins, emission velocity and expiratory duration, were controlled and measured systematically. Performances of four different types of facemask fits, varying from ideal to normal wearing practice, were also investigated. Under the pseudo-steady concentration environment, facemask protection was found to be 45 per cent, while under expiratory emissions, protection varied from 33 to 100 per cent. It was also observed that the separation between the source and the manikin was the most influential parameter affecting facemask protection.
The effects of treatment of obstructive sleep apnoea (OSA) on glucose metabolism have been investigated previously with conflicting results. This study evaluated the impact of nasal continuous ...positive airway pressure (nCPAP) treatment of OSA on insulin sensitivity. Males with moderate/severe OSA and no significant comorbidity were randomised to a therapeutic or sham nCPAP treatment group for 1 week and then reassessed. Those who received therapeutic nCPAP were further evaluated at 12 weeks. Insulin sensitivity (K(itt)) was estimated by the short insulin tolerance test. Other evaluations included blood pressure, metabolic profile, urinary catecholamines and intra-abdominal fat. In total, 61 Chinese subjects were randomised. 31 subjects receiving therapeutic nCPAP showed an increase in K(itt) (6.6+/-2.9 to 7.6+/-3.2 % x min(-1); p = 0.017), while the 30 patients on sham CPAP had no significant change, and the changes in K(itt) were different between the two groups (p = 0.022). At 12 weeks, improvement in K(itt) was seen in 20 subjects with BMI >or=25 kg x m(-2) (median (interquartile range) 28.3 (26.6-31.5); p = 0.044), but not in the nine subjects with BMI<25 kg x m(-2), or the entire group. The findings indicate that therapeutic nCPAP treatment of OSA for 1 week improved insulin sensitivity in nondiabetic males, and the improvement appeared to be maintained after 12 weeks of treatment in those with moderate obesity.
When studying the effect of weight change between two time points on a health outcome using observational data, two main problems arise initially (i) 'when is time zero?' and (ii) 'which confounders ...should we account for?' From the baseline date or the 1st follow-up (when the weight change can be measured)? Different methods have been previously used in the literature that carry different sources of bias and hence produce different results.
We utilised the target trial emulation framework and considered weight change as a hypothetical intervention. First, we used a simplified example from a hypothetical randomised trial where no modelling is required. Then we simulated data from an observational study where modelling is needed. We demonstrate the problems of each of these methods and suggest a strategy.
weight loss/gain vs maintenance.
The recommended method defines time-zero at enrolment, but adjustment for confounders (or exclusion of individuals based on levels of confounders) should be performed both at enrolment and the 1st follow-up.
The implementation of our suggested method adjusting for (or excluding based on) confounders measured both at baseline and the 1st follow-up can help researchers attenuate bias by avoiding some common pitfalls. Other methods that have been widely used in the past to estimate the effect of weight change on a health outcome are more biased. However, two issues remain (i) the exposure is not well-defined as there are different ways of changing weight (however we tried to reduce this problem by excluding individuals who develop a chronic disease); and (ii) immortal time bias, which may be small if the time to first follow up is short.
Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib is an intravenous CDK4/6 inhibitor in development to proactively ...preserve HSPC and immune system function during chemotherapy (myelopreservation). Preclinically, trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery and enhanced antitumor immunity.
This was a phase Ib (open-label, dose-finding) and phase II (randomized, double-blind placebo-controlled) study of the safety, efficacy and PK of trilaciclib in combination with etoposide/carboplatin (E/P) therapy for treatment-naive extensive-stage small-cell lung cancer patients. Patients received trilaciclib or placebo before E/P on days 1–3 of each cycle. Select end points were prespecified to assess the effect of trilaciclib on myelosuppression and antitumor efficacy.
A total of 122 patients were enrolled, with 19 patients in part 1 and 75 patients in part 2 receiving study drug. Improvements were seen with trilaciclib in neutrophil, RBC (red blood cell) and lymphocyte measures. Safety on trilaciclib+E/P was improved with fewer ≥G3 adverse events (AEs) in trilaciclib (50%) versus placebo (83.8%), primarily due to less hematological toxicity. No trilaciclib-related ≥G3 AEs occurred. Antitumor efficacy assessment for trilaciclib versus placebo, respectively, showed: ORR (66.7% versus 56.8%, P = 0.3831); median PFS 6.2 versus 5.0 m; hazard ratio (HR) 0.71; P = 0.1695; and OS (10.9 versus 10.6 m; HR 0.87; P = 0.6107).
Trilaciclib demonstrated an improvement in the patient’s tolerability of chemotherapy as shown by myelopreservation across multiple hematopoietic lineages resulting in fewer supportive care interventions and dose reductions, improved safety profile, and no detriment to antitumor efficacy. These data demonstrate strong proof-of-concept for trilaciclib’s myelopreservation benefits.
NCT02499770.
Walking and other human activities resuspend deposited pathogens from surfaces into the air, potentially leading to infection through inhaling the bioaerosols. We performed experiments in a ...laboratory chamber to quantify the pathogen resuspension from a human stepping on pathogen-seeded flooring. Three common flooring materials were chosen: carpet, vinyl tile, and hard wood. Three different types of bacteria were tested: Escherichia coli, Pseudomonas alcaligenes, and Staphylococcus epidermidis. The bacteria were first aerosolized into an experimental chamber and allowed to deposit onto the clean flooring materials, followed by a single human step on the flooring performed to resuspend the bacteria. The result showed that the resuspension emission factor (normalized parameter for the ratio of resuspended mass in the air to the mass available for resuspension on the surface during a resuspension event) of tested bacteria ranged from 3.4 × 10−5 to 2.1 × 10−4. For this study, because the resuspension mechanism is one footstep, the resuspension emission factor is also equivalent to the resuspension fraction (fraction of settled particles resuspended per footstep). The carpet consistently resulted in the highest emission factor of biological material resuspended from the surface to the air. In addition, the resuspension emission factor for Gram positive, S. epidermidis, was higher than that of the other two Gram negative bacteria for all floorings. The findings from this study provide valuable estimates for the emission of biological particles by resuspension and comparison to non-biological particles for estimating the risk of pathogen exposure in occupied environments.
•Resuspension of different bacteria from stepping on flooring was quantified for the first time.•Resuspensions of E. coli, P. alcaligenes, and S. epidermidis were measured.•Resuspension emission factors were measured for carpet, vinyl tile, and hard wood.•S. epidermidis always gave the highest resuspension among the three bacteria.
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