bluuebunny/crossref_metadata_2025 huggingface dataset:
Induction of the CtsR regulon improves Xylanase production in Bacillus subtilis
Authors: Wang Biwen , van der Kloet Frans , Hamoen Leendert W.
Published: November 2023

Background

The bacterium Bacillus subtilis is extensively used for the commercial production of enzymes due to its efficient protein secretion capacity. However, the efficiency of secretion varies greatly between enzymes, and despite many years of research, optimization of enzyme production is still largely a matter of trial-and-error. Genome-wide transcriptome analysis seems a useful tool to identify relevant secretion bottlenecks, yet to this day, only a limited number of transcriptome studies have been published that focus on enzyme secretion in B. subtilis. Here, we examined the effect of high-level expression of the commercially important enzyme endo-1,4-β-xylanase XynA on the B. subtilis transcriptome using RNA-seq.

Results

Using the novel gene-set analysis tool GINtool, we found a reduced activity of the CtsR regulon when XynA was overproduced. This regulon comprises several protein chaperone genes, including clpC, clpE and clpX, and is controlled by transcriptional repression. CtsR levels are directly controlled by regulated proteolysis, involving ClpC and its cognate protease ClpP. When we abolished this negative feedback, by inactivating the repressor CtsR, the XynA production increased by 25%.

Conclusions

Overproduction of enzymes can reduce the pool of Clp protein chaperones in B. subtilis, presumably due to negative feedback regulation. Breaking this feedback can improve enzyme production yields. Considering the conserved nature of Clp chaperones and their regulation, this method might benefit high-yield enzyme production in other organisms.
Attractive targeted sugar bait: the pyrrole insecticide chlorfenapyr and the anti-malarial pharmaceutical artemether–lumefantrine arrest Plasmodium falciparum development inside wild pyrethroid-resistant Anopheles gambiae s.s. mosquitoes
Authors: N’Guessan Raphael , Camara Soromane , Rowland Mark , Ahoua Alou Ludovic P. , Wolie Rosine Z. , Zoh Marius G. , N’Guessan Brou , Tia Innocent Z. , Oumbouke Welbeck A. , Thomas Matthew B. , Koffi Alphonsine A.
Published: November 2023

Background

Attractive targeted sugar bait (ATSB) is a novel approach to vector control, offering an alternative mode of insecticide delivery via the insect alimentary canal, with potential to deliver a variety of compounds new to medical entomology and malaria control. Its potential to control mosquitoes was recently demonstrated in major field trials in Africa. The pyrrole chlorfenapyr is an insecticide new to malaria vector control, and through its unique mode of action—disruption of ATP mediated energy transfer in mitochondria—it may have direct action on energy transfer in the flight muscle cells of mosquitoes. It may also have potential to disrupt mitochondrial function in malarial parasites co-existing within the infected mosquito. However, little is known about the impact of such compounds on vector competence in mosquitoes responsible for malaria transmission.

Methods

In this study, ATSBs containing chlorfenapyr insecticide and, as a positive control, the anti-malarial drugs artemether/lumefantrine (A/L) were compared for their effect on Plasmodium falciparum development in wild pyrethroid-resistant Anopheles gambiae sensu stricto (s.s.) and for their capacity to reduce vector competence. Female mosquitoes were exposed to ATSB containing either sublethal dose of chlorfenapyr (CFP: 0.025%) or concentrations of A/L ranging from 0.4/2.4 mg/ml to 2.4/14.4 mg/ml, either shortly before or after taking infective blood meals. The impact of their component compounds on the prevalence and intensity of P. falciparum infection were compared between treatments.

Results

Both the prevalence and intensity of infection were significantly reduced in mosquitoes exposed to either A/L or chlorfenapyr, compared to unexposed negative control mosquitoes. The A/L dose (2.4/14.4 mg/ml) totally erased P. falciparum parasites: 0% prevalence of infection in female mosquitoes exposed compared to 62% of infection in negative controls (df = 1, χ2 = 31.23 p < 0.001). The dose of chlorfenapyr (0.025%) that killed < 20% females in ATSB showed a reduction in oocyte density of 95% per midgut (0.18/3.43 per midgut).

Conclusion

These results are evidence that chlorfenapyr, in addition to its direct killing effect on the vector, has the capacity to block Plasmodium transmission by interfering with oocyte development inside pyrethroid-resistant mosquitoes, and through this dual action may potentiate its impact under field conditions.
Study on the correlation between bioelectrical impedance analysis index and protein energy consumption in maintenance dialysis patients
Authors: Wang Weina , Meng Xinxuan , Liu Jiaojiao , Lou Xiaowei , Zhang Ping , He Peipei , Chen Jianghua , Yuan Jing
Published: November 2023

Background

Protein-energy wasting (PEW) has been reported to be pretty common in maintenance dialysis patients. However, the existing PEW diagnostic standard is limited in clinical use due to the complexity of it. Bioelectrical impedance analysis (BIA), as a non-invasive nutritional assessment method, can objectively and quantitatively analyze the changes of body tissue components under different nutritional states. We aim to explore the association between PEW and BIA and establish a reliable diagnostic model of PEW.

Methods

We collected cross-sectional data of 609 maintenance dialysis patients at the First Affiliated Hospital, College of Medicine, Zhejiang University. PEW was diagnosed according to International Society of Renal Nutrition and Metabolism (ISRNM) criteria. Among them, 448 consecutive patients were included in the training set for the establishment of a diagnostic nomogram. 161 consecutive patients were included for internal validation. 52 patients from Zhejiang Hospital were included for external validation of the diagnostic model. Correlation analysis of BIA indexes with other nutritional indicators was performed. Logistic regression was used to examine the association of BIA indexes with PEW. 12 diagnostic models of PEW in maintenance dialysis patients were developed and the performance of them in terms of discrimination and calibration was evaluated using C statistics and Hosmer–Lemeshow-type χ2 statistics. After comparing to existing diagnostic models, and performing both internal and external validation, we finally established a simple but reliable PEW diagnostic model which may have great value of clinical application.

Results

A total of 609 individuals from First Affiliated Hospital, College of Medicine, Zhejiang University and 52 individuals from Zhejiang Hospital were included. After full adjustment, age, peritoneal dialysis (compared to hemodialysis), subjective global assessment (SGA, compared to non-SGA) and water ratio were independent risk factors, while triglyceride, urea nitrogen, calcium, ferritin, BCM, VFA and phase angle were independent protective factors of PEW. The model incorporated water ratio, VFA, BCM, phase angle and cholesterol revealed best performance. A nomogram was developed according to the results of model performance. The model achieved high C-indexes of 0.843 in the training set, 0.841 and 0.829 in the internal and external validation sets, respectively, and had a well-fitted calibration curve. The net reclassification improvement (NRI) showed 8%, 13%, 2%, 38%, 36% improvement of diagnostic accuracy of our model compared with “PEW score model”, “modified PEW score model”, “3-index model”, “SGA model” and “BIA decision tree model”, respectively.

Conclusions

BIA can be used as an auxiliary tool to evaluate PEW risk and may have certain clinical application value.
M2 macrophage-derived cathepsin S promotes peripheral nerve regeneration via fibroblast–Schwann cell-signaling relay
Authors: Oshima Eri , Hayashi Yoshinori , Xie Zhen , Sato Hitoshi , Hitomi Suzuro , Shibuta Ikuko , Urata Kentaro , Ni Junjun , Iwata Koichi , Shirota Tatsuo , Shinoda Masamichi
Published: November 2023

Background

Although peripheral nerves have an intrinsic self-repair capacity following damage, functional recovery is limited in patients. It is a well-established fact that macrophages accumulate at the site of injury. Numerous studies indicate that the phenotypic shift from M1 macrophage to M2 macrophage plays a crucial role in the process of axon regeneration. This polarity change is observed exclusively in peripheral macrophages but not in microglia and CNS macrophages. However, the molecular basis of axonal regeneration by M2 macrophage is not yet fully understood. Herein, we aimed to identify the M2 macrophage-derived axon regeneration factor.

Methods

We established a peripheral nerve injury model by transection of the inferior alveolar nerve (IANX) in Sprague–Dawley rats. Transcriptome analysis was performed on the injured nerve. Recovery from sensory deficits in the mandibular region and histological reconnection of IAN after IANX were assessed in rats with macrophage depletion by clodronate. We investigated the effects of adoptive transfer of M2 macrophages or M2-derived cathepsin S (CTSS) on the sensory deficit. CTSS initiating signaling was explored by western blot analysis in IANX rats and immunohistochemistry in co-culture of primary fibroblasts and Schwann cells (SCs).

Results

Transcriptome analysis revealed that CTSS, a macrophage-selective lysosomal protease, was upregulated in the IAN after its injury. Spontaneous but partial recovery from a sensory deficit in the mandibular region after IANX was abrogated by macrophage ablation at the injured site. In addition, a robust induction of c-Jun, a marker of the repair-supportive phenotype of SCs, after IANX was abolished by macrophage ablation. As in transcriptome analysis, CTSS was upregulated at the injured IAN than in the intact IAN. Endogenous recovery from hypoesthesia was facilitated by supplementation of CTSS but delayed by pharmacological inhibition or genetic silencing of CTSS at the injured site. Adoptive transfer of M2-polarized macrophages at this site facilitated sensory recovery dependent on CTSS in macrophages. Post-IANX, CTSS caused the cleavage of Ephrin-B2 in fibroblasts, which, in turn, bound EphB2 in SCs. CTSS-induced Ephrin-B2 cleavage was also observed in human sensory nerves. Inhibition of CTSS-induced Ephrin-B2 signaling suppressed c-Jun induction in SCs and sensory recovery.

Conclusions

These results suggest that M2 macrophage-derived CTSS contributes to axon regeneration by activating SCs via Ephrin-B2 shedding from fibroblasts.
Decision regret among couples experiencing infertility: a mixed methods longitudinal cohort study
Authors: Cusatis Rachel , Johnson Colin , Schoyer Katherine D. , Tsaih Shirng-Wern , Balza Joanna , Sandlow Jay , Flynn Kathryn E.
Published: November 2023

Background

Decisions for how to resolve infertility are complex and may lead to regret. We examined whether couples and individuals who sought a consultation from a reproductive specialist for infertility later expressed decisional regret about their family-building choices and whether regret was associated with parental role, family-building paths, or outcomes.

Methods

This longitudinal mixed methods study included women and their partners who completed a questionnaire prior to their initial consultation with a reproductive specialist and 6 years later. The six-year questionnaire included the Ottawa Decision Regret Scale referencing “the decisions you made about how to add a child to your family.” A score of 25+ indicates moderate-to-severe regret. Additional items invited reflections on family-building decisions, treatments, and costs. A systematic content analysis assessed qualitative themes.

Results

Forty-five couples and 34 individuals participated in the six-year questionnaire (76% retention rate), Half (n = 61) of participants expressed no regret, which was similar by role (median 0 for women and supporting partners, F = .08; p = .77). One in 5 women and 1 in 7 partners expressed moderate-to-severe regret. Women who did not pursue any treatment had significantly higher regret (median 15; F = 5.6, p < 0.01) compared to those who pursued IVF (median 0) or other treatments (median 0). Women who did not add a child to their family had significantly higher regret (median 35; F = 10.1, p < 0.001) than those who added a child through treatment (median 0), through fostering/adoption (median 0), or naturally (median 5). Among partners, regret scores were not associated with family-building paths or outcomes. More than one-quarter of participants wished they had spent less money trying to add a child to their family. Qualitative themes included gratitude for parenthood despite the burdensome process of family-building as well as dissatisfaction or regret about the process. Results should be confirmed in other settings to increase generalizability.

Conclusion

This longitudinal study provides new insight into the burden of infertility. For women seeking parenthood, any of the multiple paths to parenthood may prevent future decision regret. Greater psychosocial, financial, and decision support is needed to help patients and their partners navigate family-building with minimal regret.
Upper extremity asymmetry due to nerve injuries or central neurologic conditions: a scoping review
Authors: Bhat Sandesh G. , Shin Alexander Y. , Kaufman Kenton R.
Published: November 2023

Background

Peripheral nerve injuries and central neurologic conditions can result in extensive disabilities. In cases with unilateral impairment, assessing the asymmetry between the upper extremity has been used to assess outcomes of treatment and severity of injury. A wide variety of validated and novel tests and sensors have been utilized to determine the upper extremity asymmetry. The purpose of this article is to review the literature and define the current state of the art for describing upper extremity asymmetry in patients with peripheral nerve injuries or central neurologic conditions.

Method

An electronic literature search of PubMed, Scopus, Web of Science, OVID was performed for publications between 2000 to 2022. Eligibility criteria were subjects with neurological conditions/injuries who were analyzed for dissimilarities in use between the upper extremities. Data related to study population, target condition/injury, types of tests performed, sensors used, real-world data collection, outcome measures of interest, and results of the study were extracted. Sackett’s Level of Evidence was used to judge the quality of the articles.

Results

Of the 7281 unique articles, 112 articles met the inclusion criteria for the review. Eight target conditions/injuries were identified (Brachial Plexus Injury, Cerebral Palsy, Multiple Sclerosis, Parkinson’s Disease, Peripheral Nerve Injury, Spinal Cord Injury, Schizophrenia, and stroke). The tests performed were classified into thirteen categories based on the nature of the test and data collected. The general results related to upper extremity asymmetry were listed for all the reviewed articles. Stroke was the most studied condition, followed by cerebral palsy, with kinematics and strength measurement tests being the most frequently used tests. Studies with a level of evidence level II and III increased between 2000 and 2021. The use of real-world evidence-based data, and objective data collection tests also increased in the same period.

Conclusion

Adequately powered randomized controlled trials should be used to study upper extremity asymmetry. Neurological conditions other than stroke should be studied further. Upper extremity asymmetry should be measured using objective outcome measures like motion tracking and activity monitoring in the patient’s daily living environment.
Alcohol-attributable mortality and alcohol control policy in the Baltic Countries and Poland in 2001–2020: an interrupted time-series analysis
Authors: Radišauskas Ričardas , Štelemėkas Mindaugas , Petkevičienė Janina , Trišauskė Justina , Telksnys Tadas , Miščikienė Laura , Gobina Inese , Stoppel Relika , Reile Rainer , Janik-Koncewicz Kinga , Zatonski Witold , Lange Shannon , Tran Alexander , Rehm Jürgen , Jiang Huan
Published: November 2023

Background

The Baltic countries–Lithuania, Latvia and Estonia–are characterized by a high rate of fully alcohol-attributable mortality, compared with Poland. Alcohol control policy measures implemented since 2001 in the Baltic countries included a restriction on availability and an increase in excise taxation, among others. The aim of the current study was to evaluate the relationship between alcohol control policy implementation and alcohol-attributable mortality in the Baltic countries and Poland.

Methods

Alcohol-attributable mortality data for 2001–2020 was defined by codes 100% alcohol-attributable for persons aged 15 years and older in the Baltic countries and Poland. Alcohol control policies implemented between 2001 and 2020 were identified, and their impact on alcohol-attributable mortality was evaluated using an interrupted time-series methodology by employing a generalized additive model.

Results

Alcohol-attributable mortality was significantly higher in the Baltic countries, compared with Poland, for both males and females. In the final reduced model, alcohol control policy significantly reduced male alcohol-attributable mortality by 7.60% in the 12 months post-policy implementation. For females, the alcohol control policy mean-shift effect was higher, resulting in a significant reduction of alcohol-attributable mortality by 10.77% in the 12 months post-policy implementation. The interaction effects of countries and policy tested in the full model were not statistically significant, which indicated that the impact of alcohol control policy on alcohol-attributable mortality did not differ across countries for both males and females.

Conclusions

Based on the findings of the current study, alcohol control policy in the form of reduced availability and increased taxation was associated with a reduction in alcohol-attributable mortality among both males and females.
External context in individual placement and support implementation: a scoping review with abductive thematic analysis
Authors: Harkko Jaakko , Sipilä Noora , Nordquist Hilla , Lallukka Tea , Appelqvist-Schmidlechner Kaija , Donnelly Michael , Kouvonen Anne
Published: November 2023

Background

Context including the external context may considerably affect the adoption, implementation, sustainment, and scale-up of evidence-based practices. We investigated external contextual features by conducting a scoping review of empirical research regarding the implementation of an evidence-based psychiatric or mental health vocational rehabilitation service called Individual Placement and Support (IPS).

Methods

The protocol for the scoping review was registered with the Open Science Framework. We used the methodology by Joanna Briggs Institute for conducting the scoping review and reported it according to the PRISMA-ScR checklist. We searched 12 databases for research regarding ‘Individual Placement and Support’ or ‘Evidence-Based Supported Employment’. We retained peer-reviewed empirical studies investigating external contextual factors and their impact on IPS implementation outcomes. We extracted data from the eligible articles and conducted descriptive and thematic analyses.

Results

Fifty-nine original research papers met our eligibility requirements and were retained after reviewing 1124 titles and abstracts and 119 full texts. The analysis generated two main themes: (1) external contextual determinants of service delivery and (2) external systems influencing the evidence-to-practice process. The first main theme encompassed policies and laws, financing, and administratively instituted support resources, and organizational arrangements associated with external stakeholders that may facilitate or hinder the local implementation. The second main theme comprised strategies and actions used by different stakeholders to facilitate implementation locally or scale-up efforts at a system level.

Discussion

Our scoping review illustrates the important role that external contextual factors play and how they may facilitate or hinder the implementation and scale-up of the IPS model across mental health services in different countries. Consideration of these factors by decision-makers in mental health and welfare services, planners, providers, and practitioners is likely to facilitate the development of effective strategies for bridging the evidence-practice gap in implementing the EBPs. Finally, the scoping review identified gaps in knowledge and offered suggestions for future research.

Trial registration

Open Science Framework
PINK1-PTEN axis promotes metastasis and chemoresistance in ovarian cancer via non-canonical pathway
Authors: Zheng Fang , Zhong Jiamin , Chen Kelie , Shi Yu , Wang Fang , Wang Shengchao , Tang Song , Yuan Xiaoyu , Shen Zhangjin , Tang Sangsang , Xia Dajing , Wu Yihua , Lu Weiguo
Published: November 2023

Background

Ovarian cancer is commonly associated with a poor prognosis due to metastasis and chemoresistance. PINK1 (PTEN-induced kinase 1) is a serine/threonine kinase that plays a crucial part in regulating various physiological and pathophysiological processes in cancer cells.

Methods

The ATdb database and "CuratedOvarianData" were used to evaluate the effect of kinases on ovarian cancer survival. The gene expression in ovarian cancer cells was detected by Western blot and quantitative real-time PCR. The effects of gene knockdown or overexpression in vitro were evaluated by wound healing assay, cell transwell assay, immunofluorescence staining, immunohistochemistry, and flow cytometry analysis. Mass spectrometry analysis, protein structure analysis, co-immunoprecipitation assay, nuclear-cytoplasmic separation, and in vitro kinase assay were applied to demonstrate the PINK1-PTEN (phosphatase and tensin homolog) interaction and the effect of this interaction. The metastasis experiments for ovarian cancer xenografts were performed in female BALB/c nude mice.

Results

PINK1 was strongly associated with a poor prognosis in ovarian cancer patients and promoted metastasis and chemoresistance in ovarian cancer cells. Although the canonical PINK1/PRKN (parkin RBR E3 ubiquitin protein ligase) pathway showed weak effects in ovarian cancer, PINK1 was identified to interact with PTEN and phosphorylate it at Serine179. Remarkably, the phosphorylation of PTEN resulted in the inactivation of the phosphatase activity, leading to an increase in AKT (AKT serine/threonine kinase) activity. Moreover, PINK1-mediated phosphorylation of PTEN impaired the nuclear import of PTEN, thereby enhancing the cancer cells’ ability to resist chemotherapy and metastasize.

Conclusions

PINK1 interacts with and phosphorylates PTEN at Serine179, resulting in the activation of AKT and the inhibition of PTEN nuclear import. PINK1 promotes ovarian cancer metastasis and chemotherapy resistance through the regulation of PTEN. These findings offer new potential therapeutic targets for ovarian cancer management.
Three-dimensional architecture of granulosa cell derived from oocyte cumulus complex, revealed by FIB-SEM
Authors: Shu Chongyi , Yu Yiqi , Xiaopan Chen  , Guo Jiansheng , Zhou Yier , Wu Dandan , Yang Tianyun , Fan Yuhang , Huang Qiongxiao , Shu Jing
Published: November 2023

The oocyte cumulus complex is mainly composed of an oocyte, the perivitelline space, zona pellucida and numerous granulosa cells. The cumulus granulosa cells (cGCs) provide a particularly important microenvironment for oocyte development, regulating its growth, maturation and meiosis. In this study, we studied the internal structures and cell-to-cell connections of mouse cGCs using focused ion beam scanning electron microscopy (FIB-SEM). We reconstructed three-dimensional models to display characteristic connections between the oocyte and cGCs, and to illustrate various main organelles in cGCs together with their interaction relationship. A special form of cilium identified in granulosa cell was never reported in previous literature.
High inter-laboratory variability in the assessment of HER2-low breast cancer: a national registry study on 50,714 Danish patients
Authors: Nielsen Kåre , Sode Michael , Jensen Maj-Britt , Berg Tobias , Knoop Ann , Ejlertsen Bent , Lænkholm Anne-Vibeke
Published: November 2023

Background

Considering the recent advancements in the treatment of breast cancer with low expression of human epidermal growth factor receptor 2 (HER2), we aimed to examine inter-laboratory variability in the assessment of HER2-low breast cancer across all Danish pathology departments.

Methods

From the Danish Breast Cancer Group, we obtained data on all women diagnosed with primary invasive breast cancer in 2007–2019 who were subsequently assigned for curatively intended treatment.

Results

Of 50,714 patients, HER2 score and status were recorded for 48,382, among whom 59.2% belonged to the HER2-low group (score 1+ or 2+ without gene amplification), 26.8% had a HER2 score of 0, and 14.0% were HER2 positive. The proportion of HER2-low cases ranged from 46.3 to 71.8% among pathology departments (P < 0.0001) and from 49.3 to 65.6% over the years (P < 0.0001). In comparison, HER2 positivity rates ranged from 11.8 to 17.2% among departments (P < 0.0001) and from 12.6 to 15.7% over the years (P = 0.005). In the eight departments with the highest number of patients, variability in HER2-low cases increased from 2011 to 2019, although the same immunohistochemical assay was used. By multivariable logistic regression, the examining department was significantly related to both HER2 score 0 and HER2 positivity (P < 0.0001) but showed greater dispersion in odds ratios in the former case (range 0.25–1.41 vs. 0.84–1.27).

Conclusions

Our data showed high inter-laboratory variability in the assessment of HER2-low breast cancer. The findings cast doubt on whether the current test method for HER2 is robust and reliable enough to select HER2-low patients for HER2-targeted treatment in daily clinical practice.
p63 orchestrates serine and one carbon metabolism enzymes expression in head and neck cancer
Authors: Cappello Angela , Tosetti Giulia , Smirnov Artem , Ganini Carlo , Yang Xue , Shi Yufang , Wang Ying , Melino Gerry , Bernassola Francesca , Candi Eleonora
Published: November 2023

Background

Head and neck squamous cell carcinoma (HNSCC) is characterized by high proliferation and limited differentiation. The altered expression of the p53 family members, and specifically of p63, represents a pivotal event in the pathogenesis of HNSCC. Physiologically, p63 affects metabolism through the direct transactivation of the enzyme hexokinase 2, and subsequently controls the proliferation of epithelial cells; nonetheless, its role in cancer metabolism is still largely unclear. The high energetic demand of cancer and the consequent needs of a metabolic reshape, also involve the serine and glycine catabolic and anabolic pathways, including the one carbon metabolism (OCM), to produce energetic compounds (purines) and to maintain cellular homeostasis (glutathione and S-adenosylmethionine).

Results

The involvement in serine/glycine starvation by other p53 family members has been reported, including HNSCC. Here, we show that in HNSCC p63 controls the expression of the enzymes regulating the serine biosynthesis and one carbon metabolism. p63 binds the promoter region of genes involved in the serine biosynthesis as well as in the one carbon metabolism. p63 silencing in a HNSCC cell line affects the mRNA and protein levels of these selected enzymes. Moreover, the higher expression of TP63 and its target enzymes, negatively impacts on the overall survival of HNSCC patients.

Conclusion

These data indicate a direct role of p63 in the metabolic regulation of HNSCC with significant clinical effects.
Approximation of solutions to integro-differential time fractional order parabolic equations in $L^{p}$-spaces
Authors: Zhao Yongqiang , Tang Yanbin
Published: November 2023

In this paper we study the initial boundary value problem for a class of integro-differential time fractional order parabolic equations with a small positive parameter ε. Using the Laplace transform, Mittag-Leffler operator family, $C_{0}$

C
0

-semigroup, resolvent operator, and weighted function space, we get the existence of a mild solution. For suitable indices $p\in [1,+\infty )$
p
∈
[
1
,
+
∞
)
and $s\in (1,+\infty )$
s
∈
(
1
,
+
∞
)
, we first prove that the mild solution of the approximating problem converges to that of the corresponding limit problem in $L^{p}((0,T), L^{s}(\Omega ))$

L
p

(
(
0
,
T
)
,

L
s

(
Ω
)
)
as $\varepsilon \rightarrow 0^{+}$
ε
→

0
+

. Then for the linear approximating problem with ε and the corresponding limit problem, we give the continuous dependence of the solutions. Finally, for a class of semilinear approximating problems and the corresponding limit problems with initial data in $L^{s}(\Omega )$

L
s

(
Ω
)
, we prove the local existence and uniqueness of the mild solution and then give the continuous dependence on the initial data.
Cardiac protective techniques in left breast radiotherapy: rapid selection criteria for routine clinical decision making
Authors: Kirli Bolukbas Meltem , Karaca Sibel , Coskun Volkan , Kocak Uzel Esengul
Published: November 2023

Objective

In left breast radiotherapy (RT) desired heart doses may be achieved without heart-sparing RT techniques in some patients. We aimed to examine the existence of predictive factors and cutoff points to determine which patients are the main candidates for heart-sparing RT techniques.

Material and method

Dosimetric data for left breast cancer was examined. RT plans were made at conventional doses to the breast and peripheral lymph nodes. Statistical analyses were performed using SPSS 22.0 (SPSS Inc., IBM Corp., Armonk, NY).

Result

114 cases were evaluated by ROC (Receiver operating characteristic) analysis in the breast-conserving surgery (BCS) and mastectomy groups. While only left lung volume (AUC: 0.74, 95% CI 0.61–0.87, p = 0.002) was significant in BCS cases, in cases with mastectomy, left lung volume (AUC: 0.81, 95% CI 0.69–0.94, p = 0.002) and lung/heart volume ratio (AUC: 0.83, 95% CI 0.70–0.96, p = 0.001) had a significant relationship with the relevance of heart doses. The cutoff point of 1.92 was selected for the lung/heart volume ratio for the mastectomized patients. Moreover, the cutoff point 1154 cc and 1208 cc was determined for the left lung volume for the BCS and mastectomized patients, respectively.

Conclusion

Various cutoff points in left breast RT can be used to predict whether RT plans will meet QUANTEC (Quantitative Analysis of Normal Tissue Effects in the Clinic) heart dose limits. Evaluating only these few cutoff points before planning makes it possible to eliminate 70% of patients with BCS and 40% of patients with mastectomy from respiratory-controlled methods, which require time and effort. Patients with lung volume and lung/heart volume ratio smaller than the cutoff values can be considered primary candidates for heart-sparing techniques.
The effects of chemotherapy on resting energy expenditure, body composition, and cancer-related fatigue in women with breast cancer: a prospective cohort study
Authors: Van Soom Timia , Tjalma Wiebren , Papadimitriou Konstantinos , Gebruers Nick , van Breda Eric
Published: November 2023

Background

Breast cancer (BC) is the most prevalent tumor in women. Improvements in treatment led to declined mortality, resulting in more survivors living with cancer- or therapy-induced comorbidities. In this study, we investigated the impact of neoplasia and chemotherapy on resting energy expenditure (REE) and body composition, in relation to cancer-related fatigue. Inflammatory parameters were checked as possible explanation for changes in REE.

Methods

Fifty-six women participated: 20 women with BC and 36 healthy controls. Patients were assessed at baseline (T0) and follow-up (T1) after 12 weeks of chemotherapy. Controls were measured once. REE was assessed with indirect calorimetry: body composition (body weight, fat mass, fat-free mass) by air plethysmography. The multidimensional fatigue index (MFI-20) was used to analyze fatigue. Baseline measurements of patients were compared to results of the healthy controls with the independent-samplesT-test. The paired-samplesT-test investigated the effects of chemotherapy from T0 to T1. A Pearson correlation analysis was conducted between REE, body composition, and fatigue and between REE, body composition, and inflammatory parameters. A linear regression analysis was fitted to estimate the contribution of the significantly correlated parameters. The measured REE at T0 and T1 was compared to the predicted REE to analyze the clinical use of the latter.

Results

At baseline, patients with BC had significantly higher REE in the absence of differences in body composition. From baseline to T1, REE and body weight did not change. In contrast, fat-free mass declined significantly with concordant increase in fat mass. Fatigue deteriorated significantly. C-reactive protein at baseline predicted the change in energy expenditure. Predicted REE significantly underestimated measured REE.

Conclusions

Women with BC have higher REE in the tumor-bearing state compared to healthy controls. Chemotherapy does not affect REE but alters body composition. Predictive equations are invalid in the BC population. Results of our study can be used to implement personalized nutritional interventions to support energy expenditure and body composition and minimize long-term comorbidities.
The burden of rare variants in DPYS gene is a novel predictor of the risk of developing severe fluoropyrimidine-related toxicity
Authors: De Mattia Elena , Polesel Jerry , Silvestri Marco , Roncato Rossana , Scarabel Lucia , Calza Stefano , Spina Michele , Puglisi Fabio , Toffoli Giuseppe , Cecchin Erika
Published: November 2023

Background

Despite a growing number of publications highlighting the potential impact on the therapy outcome, rare genetic variants (minor allele frequency < 1%) in genes associated to drug adsorption, distribution, metabolism, and elimination are poorly studied. Previously, rare germline DPYD missense variants were shown to identify a subset of fluoropyrimidine-treated patients at high risk for severe toxicity. Here, we investigate the impact of rare genetic variants in a panel of 54 other fluoropyrimidine-related genes on the risk of severe toxicity.

Methods

The coding sequence and untranslated regions of 54 genes related to fluoropyrimidine pharmacokinetics/pharmacodynamics were analyzed by next-generation sequencing in 120 patients developing grade 3–5 toxicity (NCI-CTC vs3.0) and 104 matched controls. Sequence Kernel Association Test (SKAT) analysis was used to select genes with a burden of genetic variants significantly associated with risk of severe toxicity. The statistical association of common and rare genetic variants in selected genes was further investigated. The functional impact of genetic variants was assessed using two different in silico prediction tools (Predict2SNP; ADME Prediction Framework).

Results

SKAT analysis highlighted DPYS and PPARD as genes with a genetic mutational burden significantly associated with risk of severe fluoropyrimidine-related toxicity (Bonferroni adjusted P = 0.024 and P = 0.039, respectively). Looking more closely at allele frequency, the burden of rare DPYS variants was significantly higher in patients with toxicity compared with controls (P = 0.047, Mann–Whitney test). Carrying at least one rare DPYS variant was associated with an approximately fourfold higher risk of severe cumulative (OR = 4.08, P = 0.030) and acute (OR = 4.21, P = 0.082) toxicity. The burden of PPARD rare genetic variants was not significantly related to toxicity. Some common variants with predictive value in DPYS and PPARD were also identified: DPYS rs143004875-T and PPARD rs2016520-T variants predicted an increased risk of severe cumulative (P = 0.002 and P = 0.001, respectively) and acute (P = 0.005 and P = 0.0001, respectively) toxicity.

Conclusion

This work demonstrated that the rare mutational burden of DPYS, a gene strictly cooperating with DPYD in the catabolic pathway of fluoropyrimidines, is a promising pharmacogenetic marker for precision dosing of fluoropyrimidines. Additionally, some common genetic polymorphisms in DPYS and PPARD were identified as promising predictive markers that warrant further investigation.
Diet of Black-backed Jackal (Canis mesomelas, Schreber, 1775), impacts on livelihood and perceptions of farmers in Konasa Pulasa community conserved forest, omo valley of Ethiopia
Authors: Matusal Mesfin , Megaze Aberham
Published: November 2023

Background

Livestock depredation by the black-backed jackal (Canis mesomelas) occurs widely across Africa. The study on human-jackal conflict is important for conservation efforts in Ethiopia. The aim of this study was to investigate the diet of black-backed jackals, to understand their predation effects on domestic livestock and perceptions of farmers’ in the Konasa-Pulasa Community Conserved Forest, Omo Valley of Ethiopia. The study was conducted using scat analysis, questionnaire survey and Focus Group Discussion methods. Livestock depredation and the economic impact of farmers were assessed among 290 randomly selected households. A total of 90 scat samples were collected and analyzed during the dry and wet seasons to identify the diet of jackals.

Results

A total of 624 domestic animals have been lost in the last 5 years (2016–2020). The estimated economic cost of domestic animals lost due to predation by jackals was US $18,180.0 in the last five years, and US $12.5 per year per household. The major diet composition of jackals was of domestic animal origin (45.5%), followed by wild animals (30.8%) in both the dry and wet seasons. However, more prey diversity was recorded during the wet season. The respondents revealed that the causes of black-backed jackal conflict in the study area were higher due to increasing jackal population size (40%). The major traditional mitigation method was guarding (42%). Most of the respondents (48.2%) had negative perceptions towards the conservation of black-backed jackals.

Conclusion

Livestock depredations by black-backed jackals were the major issue of conflict in the study area. Scat analysis showed that large percentage of domestic animal species remain in the scat of jackals. Livestock losses caused by jackals represent an economic concern for livestock owners in the area. Local people close to the forest boundary were highly vulnerable to domestic animal loss due to predation by jackals. Therefore, improved livestock husbandry methods will be implemented by the local people for effective jackal conservation in Konasa-Pulasa Community Conserved Forest. Understanding the ecological and social dimensions of conflict situations in the area may have important ecological and management implications for the country.
Application of Metabolomics to Epidemiologic Studies of Breast Cancer: New Perspectives for Etiology and Prevention
Authors: His Mathilde , Gunter Marc J. , Keski-Rahkonen Pekka , Rinaldi Sabina
Published: November 2023

PURPOSE

To provide an overview on how the application of metabolomics (high-throughput characterization of metabolites from cells, organs, tissues, or biofluids) to population-based studies may inform our understanding of breast cancer etiology.

METHODS

We evaluated studies that applied metabolomic analyses to prediagnostic blood samples from prospective epidemiologic studies to identify circulating metabolites associated with breast cancer risk, overall and by breast cancer subtype and menopausal status. We provide some important considerations for the application and interpretation of metabolomics approaches in this context.

RESULTS

Overall, specific lipids and amino acids were indicated as the most common metabolite classes associated with breast cancer development. However, comparison of results across studies is challenging because of heterogeneity in laboratory techniques, analytical methods, sample size, and applied statistical methods.

CONCLUSION

Metabolomics is being increasingly applied to population-based studies for the identification of new etiologic hypotheses and/or mechanisms related to breast cancer development. Despite its success in applications to epidemiology, studies of larger sample size with detailed information on menopausal status, breast cancer subtypes, and repeated biologic samples collected over time are needed to improve comparison of results between studies and enhance validation of results, allowing potential clinical translation of findings.
Trastuzumab Plus Gemcitabine-Cisplatin for Treatment-Naïve Human Epidermal Growth Factor Receptor 2–Positive Biliary Tract Adenocarcinoma: A Multicenter, Open-Label, Phase II Study (TAB)
Authors: Ostwal Vikas , Mandavkar Sarika , Bhargava Prabhat , Srinivas Sujay , Kapoor Akhil , Shetty Omshree , Kannan Sadhana , Chaugule Deepali , Patil Rajshree , Parulekar Manali , Nashikkar Chaitali , Ankathi Suman Kumar , Baheti Akshay Dwarka , Mehta Daksha , Kaushal Rajiv Kumar , Yadav Subhash , Shah Aekta , Patkar Shraddha , Goel Mahesh , Ramaswamy Anant
Published: November 2023

PURPOSE

Human epidermal growth factor receptor 2 (HER2) overexpression is seen in 4%-16% of biliary tract cancers (BTCs). We aimed to evaluate the clinical activity of gemcitabine-cisplatin (GC) plus anti-HER2 antibody trastuzumab as initial treatment in HER2-positive BTCs.

METHODS

This study was an investigator-initiated, open-label, single-arm, multi-institutional, phase II trial in adult patients with HER2-positive (defined as immunohistochemistry [IHC] 3+ or IHC 2+ and fluorescent in situ hybridization–positive), treatment-naïve BTCs. The primary end point of the study was 6-month progression-free survival (PFS). Next-generation sequencing was performed on tissue samples to evaluate mutational status.

RESULTS

From March 2020 to August 2022, of the 876 screened patients, 118 (13.4%) were found to have HER2-positive status, of whom 90 were enrolled in the study. Most patients had GBC (n = 96; 96%) with two or more sites of metastatic disease (n = 70; 78%). With a median follow-up of 17.3 (95% CI, 15.22 to 19.32) months, 72 patients had disease progression with a median PFS of 7 (95% CI, 6.2 to 7.8) months. The diagnosis to event 6-month PFS rate was 75.6% (95% CI, 66.6 to 84.6). A complete or partial response was seen in 50 (55.5%) patients and 22 (24.4%) patients had stable disease as the best response to treatment, for an overall disease control rate of 80%. The presence of isolated TP53 mutations was associated with inferior PFS compared with other mutations (TERT promoter, HER2, PIK3CA, etc) or no detected mutations (6.51 v 12.02 v 10.58 months; P < .001).

CONCLUSION

The combination of GC and trastuzumab achieved its primary end point of improving PFS compared with historical data in the treatment-naïve HER2-positive BTC. Evaluating additional mutations such as TP53 and PIK3CA along with HER2 testing may help to preferentially select patients for anti-HER2 therapy in the future (Clinical Trial Registry India number: CTRI/2019/11/021955).
Multiomic Characterization Reveals a Distinct Molecular Landscape in Young-Onset Pancreatic Cancer
Authors: Ogobuiro Ifeanyichukwu , Baca Yasmine , Ribeiro Jennifer R. , Walker Phillip , Wilson Gregory C. , Gulhati Prateek , Marshall John L. , Shroff Rachna T. , Spetzler David , Oberley Matthew J. , Abbott Daniel E. , Kim Hong Jin , Kooby David A. , Maithel Shishir K. , Ahmad Syed A. , Merchant Nipun B. , Xiu Joanne , Hosein Peter J. , Datta Jashodeep
Published: November 2023

PURPOSE

Using a real-world database with matched genomic-transcriptomic molecular data, we sought to characterize the distinct molecular correlates underlying clinical differences between patients with young-onset pancreatic cancer (YOPC; younger than 50 years) and patients with average-onset pancreatic cancer (AOPC; 70 years and older).

METHODS

We analyzed matched whole-transcriptome and DNA sequencing data from 2,430 patient samples (YOPC, n = 292; AOPC, n = 2,138) from the Caris Life Sciences database (Phoenix, AZ). Immune deconvolution was performed using the quanTIseq pipeline. Overall survival (OS) data were obtained from insurance claims (n = 4,928); Kaplan-Meier estimates were calculated for age- and molecularly defined cohorts. Significance was determined as FDR-corrected P values ( Q) < .05.

RESULTS

Patients with YOPC had higher proportions of mismatch repair–deficient/microsatellite instability-high, BRCA2-mutant, and PALB2-mutant tumors compared with patients with AOPC, but fewer SMAD4-, RNF43-, CDKN2A-, and SF3B1-mutant tumors. Notably, patients with YOPC demonstrated significantly lower incidence of KRAS mutations compared with patients with AOPC (81.3% v 90.9%; Q = .004). In the KRAS wild-type subset (n = 227), YOPC tumors demonstrated fewer TP53 mutations and were more likely driven by NRG1 and MET fusions, whereas BRAF fusions were exclusively observed in patients with AOPC. Immune deconvolution revealed significant enrichment of natural killer cells, CD8+ T cells, monocytes, and M2 macrophages in patients with YOPC relative to patients with AOPC, which corresponded with lower rates of HLA-DPA1 homozygosity. There was an association with improved OS in patients with YOPC compared with patients with AOPC with KRAS wild-type tumors (median, 16.2 [YOPC- KRASWT] v 10.6 [AOPC- KRASWT] months; P = .008) but not KRAS-mutant tumors ( P = .084).

CONCLUSION

In this large, real-world multiomic characterization of age-stratified molecular differences in pancreatic ductal adenocarcinoma, YOPC is associated with a distinct molecular landscape that has prognostic and therapeutic implications.
Recurrent Soft Tissue Infections Associated With Burosumab Therapy in X-Linked Hypophosphatemic Rickets
Authors: Yoon Sean Ho , Passarella Pasquale
Published: November 2023

X-linked hypophosphatemic rickets (XLH) is a genetic disorder characterized by elevated fibroblast growth factor 23 (FGF23), resulting in renal phosphate wasting and inadequate bone mineralization. Burosumab, a monoclonal antibody that inhibits FGF23 activity, has shown promise in improving renal phosphate reabsorption and clinical outcomes in XLH patients. However, the potential side effects of burosumab, particularly its impact on immune function and susceptibility to infections, remain a subject of concern. In this case report, we describe a 57-year-old male individual with XLH who experienced recurrent soft tissue infections while receiving burosumab therapy. The infections included an olecranon abscess, a cervical retropharyngeal phlegmon with a sternocleidomastoid abscess, and suprapubic cellulitis, all of which were treated with antibiotic therapy. Following discontinuation of burosumab therapy, the patient did not experience further soft tissue infections. These observations suggest a potential association between burosumab therapy and an increased risk of soft tissue infections. Mechanistically, disruption of the FGF23-Klotho signaling axis may lead to impaired humoral immunity mediated by B lymphocytes and compromised innate immune response mediated by macrophages. Further investigation is warranted to better understand the immunological effects of burosumab and its implications for infectious complications in XLH patients.