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BioRxiv : the Preprint Server For... Jun 2024has emerged as a frontrunner among deadly fungal pathogens and is particularly life-threatening for many HIV-infected individuals with compromised immunity. Multiple...
UNLABELLED
has emerged as a frontrunner among deadly fungal pathogens and is particularly life-threatening for many HIV-infected individuals with compromised immunity. Multiple virulence factors contribute to the growth and survival of within the human host, the two most prominent of which are the polysaccharide capsule and melanin. As both of these features are associated with the cell wall, we were interested to explore possible cooperative or competitive interactions between these two virulence factors. Whereas capsule thickness had no effect on the rate at which cells became melanized, build-up of the melanin pigment layer resulted in a concomitant loss of polysaccharide material, leaving melanized cells with significantly thinner capsules than their non-melanized counterparts. When melanin was provided exogenously to cells in a transwell culture system we observed a similar inhibition of capsule growth and maintenance. Our results show that melanin sequesters calcium thereby limiting its availability to form divalent bridges between polysaccharide subunits required for outer capsule assembly. The decreased ability of melanized cells to incorporate exported polysaccharide into the growing capsule correlated with the amount of shed polysaccharide, which could have profound negative impacts on the host immune response.
SIGNIFICANCE STATEMENT
is an opportunistic fungal pathogen that presents a significant health risk for immunocompromised individuals. We report an interaction between the two major cryptococcal virulence factors, the polysaccharide capsule and melanin. Melanin impacted the growth and maintenance of the polysaccharide capsule, resulting in loss of capsular material during melanization. Our results suggest that melanin can act as a sink for calcium, thereby limiting its availability to form ionic bridges between polysaccharide chains on the growing surface of the outer capsule. As polysaccharide is continuously exported to support capsule growth, failure of melanized cells to incorporate this material results in a higher concentration of shed polysaccharide in the extracellular milieu, which is expected to interfere with host immunity.
PubMed: 38948764
DOI: 10.1101/2024.06.20.599928 -
BioRxiv : the Preprint Server For... Jun 2024Flagella are highly complex rotary molecular machines that enable bacteria to not only migrate to optimal environments but to also promote range expansion,...
Flagella are highly complex rotary molecular machines that enable bacteria to not only migrate to optimal environments but to also promote range expansion, competitiveness, virulence, and antibiotic survival. Flagellar motility is an energy-demanding process, where the sum of its production (biosynthesis) and operation (rotation) costs has been estimated to total ∼10% of the entire energy budget of an cell. The acquisition of such a costly adaptation process is expected to secure short-term benefits by increasing competitiveness and survival, as well as long-term evolutionary fitness gains. While the role of flagellar motility in bacterial survival has been widely reported, its direct influence on the rate of evolution remains unclear. We show here that both production and operation costs contribute to elevated mutation frequencies. Our findings suggest that flagellar movement may be an important player in tuning the rate of bacterial evolution.
PubMed: 38948722
DOI: 10.1101/2024.06.21.600093 -
Cancer Management and Research 2024As one of the most important breakthroughs in cancer therapy, immune checkpoint inhibitors have greatly prolonged survival of patients with breast cancer. However, their...
Efficacy and Safety of Chidamide in Combination with PD-1 Inhibitor and Radiotherapy for HER2-Negative Advanced Breast Cancer: Study Protocol of a Single Arm Prospective Study.
PURPOSE
As one of the most important breakthroughs in cancer therapy, immune checkpoint inhibitors have greatly prolonged survival of patients with breast cancer. However, their application and efficacy are limited, especially for advanced HER2-negative breast cancer. It has been reported that epigenetic modulation of the histone deacetylase (HDAC) inhibitor chidamide, as well as immune microenvironment modulation of radiotherapy are potentially synergistic with immunotherapy. Thus, the combination of chidamide, radiotherapy and immunotherapy is expected to improve prognosis of patients with advanced HER2-negative breast cancer.
PATIENTS AND METHODS
This is a single-arm, open, prospective clinical trial investigating the efficacy and safety of the combination of HDAC inhibitor chidamide, anti-PD-1 antibody sintilimab, and the novel immuno-radiotherapy, which aims to enhance efficacy of immunotherapy, in subsequent lines of therapy of HER2-negative breast cancer. Our study will include 35 patients with advanced breast cancer that has failed endocrine therapy and first-line chemotherapy. Participants will receive 30 mg of chidamide twice a week, 200 mg of sintilimab once every 3 weeks, combined with immuno-radiotherapy. Radiotherapy will be centrally 8 Gy for at least one lesion, and at least 1 Gy for the other lesions. We will complete three fractions of radiotherapy in one cycle. The primary endpoint is progression-free survival, and secondary endpoints are objective response rate, disease control rate and safety. Moreover, biomarkers including cytokines and lymphocyte subgroups will be explored.
CONCLUSION
As a single-arm clinical trial, the analysis of the influence of each single treatment is limited. Besides, our study is an open study, which involves neither randomization nor blinding. In spite of the abovementioned limitations, this prospective clinical trial will give an insight into subsequent lines of therapy of HER2-negative advanced breast cancer, prolong the survival or achieve long remission for these participants, and identify potential responders.
PubMed: 38948681
DOI: 10.2147/CMAR.S464677 -
Journal of Family Medicine and Primary... May 2024Recent disease resurgence in China indicates that corona virus infectious disease is still a pertinent public health problem. We stand at a juncture where we are still...
Association of socio-demographic factors with clinical outcome among hospitalized patients in first and second waves of COVID-19 pandemic: Study from the developing world.
BACKGROUND
Recent disease resurgence in China indicates that corona virus infectious disease is still a pertinent public health problem. We stand at a juncture where we are still unsure about the initial dilemmas regarding its birth, therapies, and the emerging novel strains. Medical literature has focused on the clinical, laboratory, radiological, and therapeutic aspects of disease management. There is paucity of literature on the association between socio-demographic variables on disease severity and clinical outcome.
MATERIALS AND METHODS
This retrospective observational study analyzing the socio-demographic variables was performed at a dedicated COVID care center in western Maharashtra, India. Electronic records of all individuals who were admitted to this hospital from July 29 2020, to June 14, 2021, and diagnosed COVID-19 positive by reverse transcriptase polymerase chain reaction (RT-PCR) were identified after due institutional ethical clearance. Patients admitted from July 29, 2020, to February 27, 2021, were categorized as patients presenting during the 'first wave of viral pandemic'. Those admitted from March 01, 2021, to June 14, 2021, have been included as patients admitted during 'second wave of viral pandemic'. The following outcome parameters were collected (presenting symptoms, duration of symptoms before the individual presented for diagnostic RT-PCR, total duration of symptoms, severity of disease at onset, duration of hospital stay, the final outcome (discharge/death) and Charlson's comorbidity index). The linear regression model was used to establish association between socio-demographic factors and disease severity at onset (mild/moderate/severe/critical).
RESULTS
A total of 37033 patients were screened, and the positivity rate with RT-PCR was 16.99% ( = 6275) during the study period. Out of which 45% ( = 2824) of the patients had mild disease requiring home isolation and the remaining 55% of patients required admission. 1590 patients from the first wave and 910 from the second wave of COVID-19 were hospitalized and included in the study after exclusion. The mean age of patients in first wave was 49 years and that in second wave was 54 years with 77.6% and 70.6% males in two waves, respectively. The burden of critical cases was higher in second wave as computed to first wave (10% vs 8%). The second wave had more outreach in the rural population as compared to second one (17.8% vs 12.2%). The mean duration from the onset of symptoms to hospitalization was 03 and 04 days, respectively, in two waves. Mortality associated in two waves was 11.9% and 24%, respectively ( < 0.05). Higher Charlson's comorbidity index was associated with higher mortality, and the cumulative survival from urban area was more as compared to the rural population (log rank - 9.148, = 0.0002).
CONCLUSION
The second COVID-19 wave had significantly higher case mortality. It affected elderly patients and those with rural background. The factors associated with higher mortality during COVID-19 pandemic were rural background, higher Charlson's comorbidity index and late presentation to the hospital. Ongoing vaccine campaigns, thus, should focus on rural areas and individuals with comorbidities especially in developing and least developed countries.
PubMed: 38948593
DOI: 10.4103/jfmpc.jfmpc_57_23 -
Frontiers in Endocrinology 2024Medullary thyroid cancer (MTC) is a challenging malignancy. The survival outcome of MTC based on AJCC staging system does not render a discriminant classifier among...
BACKGROUND
Medullary thyroid cancer (MTC) is a challenging malignancy. The survival outcome of MTC based on AJCC staging system does not render a discriminant classifier among early stages.
METHODS
3601 MTC patients from 2000 to 2018 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Smooth curve fitting, Cox proportional hazard regression and competing risk analysis were applied.
RESULTS
A linear correlation between age and log RR (relative risk of overall death) was detected. Overlaps were observed between K-M curves representing patients aged 45-50, 50-55, and 55-60. The study cohort was divided into 3 subgroups with 2 age cutoffs set at 45 and 60. Each further advanced age cutoff population resulted in a roughly "5%" increase in MTC-specific death risks and an approximately "3 times" increase in non-MTC-specific death risks.
CONCLUSIONS
The survival outcome disparity across age cutoffs at 45 and 60 for MTC has been well defined.
Topics: Humans; Thyroid Neoplasms; Middle Aged; Male; Female; Carcinoma, Neuroendocrine; Retrospective Studies; Age Factors; SEER Program; Survival Rate; Aged; Prognosis; Adult; Cohort Studies; Follow-Up Studies
PubMed: 38948527
DOI: 10.3389/fendo.2024.1393904 -
Frontiers in Endocrinology 2024Increased levels of serum Klotho have been associated with a reduced risk of several cardiovascular diseases (CVD). However, limited studies exist on the association...
BACKGROUND
Increased levels of serum Klotho have been associated with a reduced risk of several cardiovascular diseases (CVD). However, limited studies exist on the association between serum Klotho and mortality in patients with CVD.
METHODS
We collected data from CVD patients in the National Health and Nutrition Examination Survey (NHANES) spanning 2007 to 2016. We linked NHANES data with the National Death Index to determine the survival status of participants. Univariate and multivariable Cox regression models were used to investigate the relationship between serum Klotho levels and mortality in CVD patients. The relationship between serum Klotho quartiles and mortality in CVD patients was visualized using Kaplan-Meier (KM) curves and restricted cubic spine. Finally, subgroup analyses were used to examine the association between serum Klotho and all-cause mortality in different populations.
RESULTS
1905 patients with CVD were finally enrolled in our study with a mean follow-up of 7.1 years. The average age of the participants was 63.4 years, with 58.40% being male. KM showed that lower Klotho levels were associated with lower survival rates. After adjusting for potential confounders, patients with higher serum Klotho levels had lower all-cause mortality (Q1: 1.00, Q2: 0.58 (0.42-0.80), Q3: 0.69 (0.47-1.01), and Q4:0.64 (0.45-0.92). However, the relationship between serum Klotho levels and cardiovascular mortality was not statistically significant. Dose-response analysis shows a U-shaped relationship between serum Klotho levels and all-cause mortality in patients with CVD (P nonlinear=0.002). Subgroup analysis indicated that participants with a history of hypertension had a higher risk of all-cause mortality in serum Klotho Q4 compared to Q1 (P trend <0.05).
CONCLUSION
The relationship between serum Klotho levels and all-cause mortality in CVD patients exhibits a U-shaped association. The underlying mechanisms of this association need further investigation.
Topics: Humans; Klotho Proteins; Male; Female; Cardiovascular Diseases; Middle Aged; Prospective Studies; Aged; United States; Nutrition Surveys; Glucuronidase; Biomarkers; Cause of Death; Follow-Up Studies; Survival Rate
PubMed: 38948524
DOI: 10.3389/fendo.2024.1405665 -
Journal of Orthopaedics Nov 2024Short stem prostheses were originally designed for younger and more active patients. In recent years, they have been increasingly offered to older patients. This study...
INTRODUCTION
Short stem prostheses were originally designed for younger and more active patients. In recent years, they have been increasingly offered to older patients. This study evaluates the mid-to long-term survival of a short stem prosthesis and the changes in periprosthetic bone density following implantation of a cementless short hip stem in patients over 60 years of age.
METHODS
118 patients aged over 60 received short stem prostheses. Clinical examination included Harris Hip Score (HHS) and Hip Disability and Osteoarthritis Outcome Score (HOOS). 93 patients were followed clinically for at least five years. 53 patients underwent dual-energy x-ray absorptiometry (DXA) and radiographic evaluation. Follow-up intervals were preoperative and postoperative (t), at approximately six months (t), at approximately two years (t), and at approximately five years or later (t).
RESULTS
Over a mean 6.7-year observation period for all 118 patients, one stem revision occurred due to a traumatic periprosthetic stem fracture. The five-year survival rate for the endpoint in 95 at-risk patients is 99.2%. HHS improved significantly from t 55.3 ± 11.5 (range 30-79) to t 95.3 ± 8.6 (range 57-100) at a mean of 8.0 years (p < 0.001). HOOS improved significantly in each subscale (p < 0.001). Bone mineral density (BMD) was available for review in 53 patients after a mean of 7.1 years. BMD increased from t to t in region of interest (ROI) 3 (+0.4%) and ROI 6 (+2.9%) and decreased in ROI 1 (-10.3%), ROI 2 (-9.8%), ROI 4 (-5.3%), ROI 5 (-3.4%) and ROI 7 (-23.1%).
CONCLUSIONS
The evaluated short stem prosthesis shows a remarkably high survival rate in elderly patients, accompanied by excellent clinical results. Load transfer measurements show a metaphyseal-diaphyseal pattern with a trend towards increased diaphyseal transfer over the period observed.
PubMed: 38948502
DOI: 10.1016/j.jor.2024.06.003 -
Frontiers in Surgery 2024Over the course of nearly six decades since the inception of initial trials involving 5-FU in the treatment of mCRC (metastatic colorectal cancer), our progressive... (Review)
Review
Over the course of nearly six decades since the inception of initial trials involving 5-FU in the treatment of mCRC (metastatic colorectal cancer), our progressive comprehension of the pathophysiology, genetics, and surgical techniques related to mCRC has paved the way for the introduction of novel therapeutic modalities. These advancements not only have augmented the overall survival but have also positively impacted the quality of life (QoL) for affected individuals. Despite the remarkable progress made in the last two decades in the development of chemotherapy, immunotherapy, and target therapies, mCRC remains an incurable disease, with a 5-year survival rate of 14%. In this comprehensive review, our primary goal is to present an overview of mCRC treatment methods following the latest guidelines provided by the National Comprehensive Cancer Network (NCCN), the American Society of Clinical Oncology (ASCO), and the American Society of Colon and Rectal Surgeons (ASCRS). Emphasis has been placed on outlining treatment approaches encompassing chemotherapy, immunotherapy, targeted therapy, and surgery's role in managing mCRC. Furthermore, our review delves into prospective avenues for developing new therapies, offering a glimpse into the future of alternative pathways that hold potential for advancing the field.
PubMed: 38948479
DOI: 10.3389/fsurg.2024.1398289 -
Frontiers in Pharmacology 2024Genomic profiling has revolutionized therapeutic interventions and the clinical management of liver cancer. However, pathogenetic mechanisms, molecular determinants of...
Genomic profiling has revolutionized therapeutic interventions and the clinical management of liver cancer. However, pathogenetic mechanisms, molecular determinants of recurrence, and predictive biomarkers for first-line treatment (anti-PD-(L)1 plus bevacizumab) in liver cancer remain incompletely understood. Targeted next-generation sequencing (tNGS) (a 603-cancer-gene panel) was applied for the genomic profiling of 232 hepatocellular carcinoma (HCC) and 22 intrahepatic cholangiocarcinoma (ICC) patients, among which 47 unresectable/metastatic HCC patients underwent anti-PD-1 plus bevacizumab therapy. Genomic alterations were estimated for their association with vascular invasion (VI), location of onset, recurrence, overall survival (OS), recurrence-free survival (RFS), and anti-PD-1 plus bevacizumab therapy response. The genomic landscape exhibited that the most commonly altered genes in HCC were , , , , , and , while , , , , , and were frequently altered in ICC; notably, (18.18% vs. 1.29%) and (13.64% vs. 1.29%) alterations were significantly more prevalent in ICC. Comparison analysis demonstrated the distinct clinicopathological/genomic characterizations between Chinese and Western HCC cohorts. Genomic profiling of HCC underlying VI showed that , , , , and were frequently altered in the VI group compared to patients without VIs. Compared to the right hepatic lobes of HCC patients, the left hepatic lobe of HCC patients had superior OS (median OS: 36.77 months vs. unreached, < 0.05). By further comparison, Notch signaling pathway-related alterations were significantly prevalent among the right hepatic lobes of HCC patients. Of note, multivariate Cox regression analysis showed that altered , , , , and , as independent prognostic factors, were significantly correlated with the OS of HCC patients. Furthermore, altered was abundantly enriched in the HCC-recurrent group, and impressively, it was independent of clinicopathological features in predicting RFS (median RFS of altered type vs. wild-type: 5.57 months vs. 22.47 months, < 0.01). Regarding those treated HCC patients, TMB value, altered , and cell cycle-related alterations were identified to be positively associated with the objective response rate (ORR), but alterations were negatively correlated with ORR. In addition, altered and cell cycle signaling were significantly associated with reduced and increased time to progression-free survival (PFS), respectively. Comprehensive genomic profiling deciphered distinct molecular characterizations underlying VI, location of onset, recurrence, and survival time in liver cancer. The identification of novel genetic predictors of response to anti-PD-1 plus bevacizumab in HCC facilitated the development of an evidence-based approach to therapy.
PubMed: 38948469
DOI: 10.3389/fphar.2024.1416295 -
Lancet Regional Health. Americas Jul 2024This study determined the impact of pre-operative abdominal MRI on all-cause mortality for patients with resected PDAC.
BACKGROUND
This study determined the impact of pre-operative abdominal MRI on all-cause mortality for patients with resected PDAC.
METHODS
All adult (≥18 years) PDAC patients who underwent pancreatectomy between January 2011 and December 2022 in Ontario, Canada, were identified for this population-based cohort study (ICD-O-3 codes: C250, C251, C252, C253, C257, C258). Patient demographics, comorbidities, PDAC stage, medical and surgical management, and survival data were sourced from multiple linked provincial administrative databases at ICES. All-cause mortality was compared between patients with and without a pre-operative abdominal MRI after controlling for multiple covariates.
FINDINGS
A cohort of 4579 patients consisted of 2432 men (53.1%) and 2147 women (46.9%) with a mean age of 65.2 years (standard deviation: 11.2 years); 2998 (65.5%) died while 1581 (34.5%) survived. Median follow-up duration post-resection was 22.4 months (interquartile range: 10.8-48.8 months), and median survival post-pancreatectomy was 25.9 months (95% confidence interval [95% CI]: 24.8, 27.5). Patients who underwent a pre-operative abdominal MRI had a median survival of 33.1 months (95% CI: 30.7, 37.2) compared to 21.1 months (95% CI: 19.8, 22.6) for all others. A total of 2354/4579 (51.4%) patients underwent a pre-operative abdominal MRI, which was associated with a 17.2% (95% CI: 11.0, 23.1) decrease in the rate of all-cause mortality, with an adjusted hazard ratio (aHR) of 0.828 (95% CI: 0.769, 0.890).
INTERPRETATION
Pre-operative abdominal MRI was associated with improved overall survival for PDAC patients who underwent pancreatectomy, possibly due to better detection of liver metastases than CT.
FUNDING
Northern Ontario Academic Medicine Association (NOAMA) Clinical Innovation Fund.
PubMed: 38948322
DOI: 10.1016/j.lana.2024.100809