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Background: Postural neck pain is a prevalent condition characterized by neck discomfort, occurring in the absence of notable tissue damage or trauma. Individuals afflicted by this condition typically encounter an ache or pain when engaging in activities that impose prolonged stress on normal tissue. Poor posture is often the root cause of strained neck muscles, leading to the manifestation of neck pain. Moreover, it is important to recognize that neck pain can also serve as an indication of more severe underlying issues. In particular, the combination of poor posture and age-related wear and tear has been found to be associated with neck pain Objective: The present study aimed to determine the prevalence of postural neck pain among undergraduate female students of BIHS Islamabad. Material & Methods: A descriptive cross-sectional study was conducted using demographic data, Numeric pain rating scale (NPRS), Occiput to wall distance (OWD) test and Neck disability index (NDI) to determine the prevalence of postural neck pain among undergraduate female students. The study participants were the female students of BIHS, age between 18 to 30 years. Data collection tools used were numeric pain rating scale for pain variable and Neck Disability Index for assessing the restrictions in daily activities due to neck pain. Data was analyzed through Frequency Tables in SPSS version 21. Results: The present study showed the prevalence of postural Neck pain among undergraduate students of BIHS Islamabad based on analysis. This study included 115 participants within an age range of 15 to 30 years. 65 (56.52%) out of 115 participants suffered postural neck pain. The maximum of the participants was from the age group of 18 to 20 years and the most adopted posture from the participants for study purpose was sitting that was 104 (90.4%) following the lying posture 11 (9.6%). Numeric pain rating scale revealed that maximum of the participants 50 (43.5%) had moderate amount of pain following the mild pain that was 49 (42.6%). The responses from the neck disability index questionnaire showed that 73 (63.5%) participants had mild neck disability following moderate disability that was 33 (28.7). Conclusion: This study serves as a significant contribution to the existing body of knowledge, elucidating the distressing prevalence of postural neck pain and its detrimental effects on the functional capacities and overall quality of life of female undergraduate students.

Supplementary Figure from Ovarian Cancers with Low CIP2A Tumor Expression Constitute an APR-246–Sensitive Disease Subtype

Identification of ovarian cancer patient subpopulations with increased sensitivity to targeted therapies could offer significant clinical benefit. We report that 22% of the high-grade ovarian cancer tumors at diagnosis express CIP2A oncoprotein at low levels. Furthermore, regardless of their significantly lower likelihood of disease relapse after standard chemotherapy, a portion of relapsed tumors retain their CIP2A-deficient phenotype. Through a screen for therapeutics that would preferentially kill CIP2A-deficient ovarian cancer cells, we identified reactive oxygen species inducer APR-246, tested previously in ovarian cancer clinical trials. Consistent with CIP2A-deficient ovarian cancer subtype in humans, CIP2A is dispensable for development of MISIIR-Tag–driven mouse ovarian cancer tumors. Nevertheless, CIP2A-null ovarian cancer tumor cells from MISIIR-Tag mice displayed APR-246 hypersensitivity both in vitro and in vivo. Mechanistically, the lack of CIP2A expression hypersensitizes the ovarian cancer cells to APR-246 by inhibition of NF-κB activity. Accordingly, combination of APR-246 and NF-κB inhibitor compounds strongly synergized in killing of CIP2A-positive ovarian cancer cells. Collectively, the results warrant consideration of clinical testing of APR-246 for CIP2A-deficient ovarian cancer tumor subtype patients. Results also reveal CIP2A as a candidate APR-246 combination therapy target for ovarian cancer.

Supplementary Table from Ovarian Cancers with Low CIP2A Tumor Expression Constitute an APR-246–Sensitive Disease Subtype

Supplementary Data from Ovarian Cancers with Low CIP2A Tumor Expression Constitute an APR-246–Sensitive Disease Subtype

Basal-like breast cancers (BLBC) are characterized by defects in homologous recombination (HR), deficient mitotic checkpoint, and high-proliferation activity. Here, we discover CIP2A as a candidate driver of BLBC. CIP2A was essential for DNA damage–induced initiation of mouse BLBC-like mammary tumors and for survival of HR–defective BLBC cells. CIP2A was dispensable for normal mammary gland development and for unperturbed mitosis, but selectively essential for mitotic progression of DNA damaged cells. A direct interaction between CIP2A and a DNA repair scaffold protein TopBP1 was identified, and CIP2A inhibition resulted in enhanced DNA damage–induced TopBP1 and RAD51 recruitment to chromatin in mammary epithelial cells. In addition to its role in tumor initiation, and survival of BRCA-deficient cells, CIP2A also drove proliferative MYC and E2F1 signaling in basal-like triple-negative breast cancer (BL-TNBC) cells. Clinically, high CIP2A expression was associated with poor patient prognosis in BL-TNBCs but not in other breast cancer subtypes. Small-molecule reactivators of PP2A (SMAP) inhibited CIP2A transcription, phenocopied the CIP2A-deficient DNA damage response (DDR), and inhibited growth of patient-derived BLBC xenograft. In summary, these results demonstrate that CIP2A directly interacts with TopBP1 and coordinates DNA damage–induced mitotic checkpoint and proliferation, thereby driving BLBC initiation and progression. SMAPs could serve as a surrogate therapeutic strategy to inhibit the oncogenic activity of CIP2A in BLBCs.Significance:These results identify CIP2A as a nongenetic driver and therapeutic target in basal-like breast cancer that regulates DNA damage–induced G2–M checkpoint and proliferative signaling.

Supplementary Data from CIP2A Interacts with TopBP1 and Drives Basal-Like Breast Cancer Tumorigenesis

Basal-like breast cancers (BLBC) are characterized by defects in homologous recombination (HR), deficient mitotic checkpoint, and high-proliferation activity. Here, we discover CIP2A as a candidate driver of BLBC. CIP2A was essential for DNA damage–induced initiation of mouse BLBC-like mammary tumors and for survival of HR–defective BLBC cells. CIP2A was dispensable for normal mammary gland development and for unperturbed mitosis, but selectively essential for mitotic progression of DNA damaged cells. A direct interaction between CIP2A and a DNA repair scaffold protein TopBP1 was identified, and CIP2A inhibition resulted in enhanced DNA damage–induced TopBP1 and RAD51 recruitment to chromatin in mammary epithelial cells. In addition to its role in tumor initiation, and survival of BRCA-deficient cells, CIP2A also drove proliferative MYC and E2F1 signaling in basal-like triple-negative breast cancer (BL-TNBC) cells. Clinically, high CIP2A expression was associated with poor patient prognosis in BL-TNBCs but not in other breast cancer subtypes. Small-molecule reactivators of PP2A (SMAP) inhibited CIP2A transcription, phenocopied the CIP2A-deficient DNA damage response (DDR), and inhibited growth of patient-derived BLBC xenograft. In summary, these results demonstrate that CIP2A directly interacts with TopBP1 and coordinates DNA damage–induced mitotic checkpoint and proliferation, thereby driving BLBC initiation and progression. SMAPs could serve as a surrogate therapeutic strategy to inhibit the oncogenic activity of CIP2A in BLBCs. Significance: These results identify CIP2A as a nongenetic driver and therapeutic target in basal-like breast cancer that regulates DNA damage–induced G2–M checkpoint and proliferative signaling.

SHARPIN is involved in several cellular processes and promotes cancer progression. However, how the choice between different functions of SHARPIN is post-translationally regulated is unclear. Here, we characterized SHARPIN phosphorylation by mass spectrometry and in vitro kinase assay. Focusing on S131 and S146, we demonstrate that they have a role in SHARPIN-ARP2/3 complex interaction, but play no role in integrin inhibition or LUBAC activation. Consistent with its novel role in ARP2/3 regulation, S146 phosphorylation of SHARPIN promoted lamellipodia formation. We also demonstrate that SHARPIN S146 phosphorylation-mediated ARP2/3 interaction is sensitive to inhibition of ERK1/2 or reactivation of protein phosphatase 2A (PP2A). Notably, CRISPR/Cas9-mediated knockout of SHARPIN abrogated three-dimensional (3D) invasion of several cancer cell lines. The 3D invasion of cancer cells was rescued by overexpression of the wild-type SHARPIN, but not by SHARPIN S146A mutant. Finally, we demonstrate that inhibition of phosphorylation at S146 significantly reduces in vivo metastasis in a zebrafish model. Collectively, these results map SHARPIN phosphorylation sites and identify S146 as a novel phosphorylation switch defining ARP2/3 interaction and cancer cell invasion. This article has an associated First Person interview with the first author of the paper.

The adaptor protein SHARPIN is involved in a number of cellular processes and promotes cancer progression and metastasis. However, how the choice between different functions of SHARPIN is post-translationally regulated is unclear. Here we have characterized SHARPIN phosphorylation by mass spectrometry and in vitro kinase assay. Focusing on two uncharacterized phosphorylation sites, serine 131 and 146, in the unstructured linker region of SHARPIN, we demonstrate their role in SHARPIN-ARP2/3 complex interaction, whereas they play no role in integrin inhibition or LUBAC activation. Consistent with its novel role in ARP2/3 regulation, serine 146 (S146) phosphorylation of SHARPIN promoted lamellopodia formation. Notably, CRISPR-Cas9 mediated knockout of SHARPIN abrogated three-dimensional (3D) invasion of several cancer cell lines. The 3D invasion of cancer cells was rescued by overexpression of the wild-type SHARPIN, but not by SHARPIN S146A mutant, identifying S146 as an invasion promoting phosphorylation switch. Finally, we demonstrate that inhibition of phosphorylation at S146 significantly reduces the in vivo metastasis in the zebrafish model. Collectively, these results demonstrate that SHARPIN S146 phosphorylation constitutes a single functional determinant of cancer cell invasion both in vitro and in vivo.

Treatment of major depression disorder with Selective serotonin reuptake inhibitors (SSRIs), such as citalopram (CTM), during pregnancy effects on the neurological trajectory of the offspring and induces enduring consequences, notably emotional and cognitive impairment. The associations between prenatal exposure to SSRIs and neurological underpinnings of these atypical behaviors in offspring are contentious and poorly understood.We examined modifications in physiological, morphological, and biochemical characteristics in male and female offspring of C57BL/6 exposed to CTM during the third trimester of gestation. We utilized different behavior procedures to observe depression and anxiety-like behavior in 1~2 month old CTM-exposed mouse offspring. We employed Golgi-Cox staining to examine the neuronal structure of medial prefrontal cortex (mPFC) in CTM-exposed mice following protein expression levels by utilizing biochemical techniques.Our results indicate an impaired behavior such as anxiety and altered locomotion along with the substantial reduction in dendritic length and the number of dendritic branches in CTM-exposed mice. We observed differentially increase c-Fos expression in the mPFC following altered protein expression levels relative to controls.Our finding supports the function of CTM as a prenatal modulator of susceptibility to depressive-like behavior in offspring. We indicate that prenatal CTM exposure elicits a negative impact on the central nervous system, especially those regions involved in cognition and drug reinforcement. Furthermore, genetic, chemo-genetic, and optogenetic methods should be used to explain the function of SSRIs such as CTM during pregnancy in the regulation of mood and emotion-related behaviors in children.

In this paper we explore the static trade-off theory of capital structure under different governance structures. We find that good governance firms have leverage ratios that are higher (forty-seven percent) than poor governance firms per unit of profit. Evidence also suggests that while the leverage ratio for good governance firms has a narrower range and adjusts with changes in profit, the same is not true for poor governance firms. Direct test of the theory finds that good governance firms exhibit a positive relationship between profits and leverage, while poor governance firms show an inverse relationship. Further tests provide evidence for the varying use of tangible assets and size in leverage increasing activities for the two classifications of firms. The results of the paper demonstrate that the mixed results of prior studies notwithstanding, leverage is increasing in profits when controlled for agency problems, and shareholder-controlled firms exhibit the results predicted by the theory.

This article empirically shows that the cost of new debt is higher for firms that commit covenant violations. Using a proxy for product market competition to capture exogenous changes to a firm’s competitive environment, I find that the cost is systematically higher for firms that operate in competitive markets. Moreover, I identify channels through which violations can increase the cost of new debt, namely, the incidence, timing and frequency effects, and I document these effects to be more acute for competitive markets. Overall, the study finds that the market prices financial contracts by taking into account the information content of the violation and the risk arising from market competition. JEL Classification: G12, G30

Identification of ovarian cancer (OvCa) patient subpopulations with increased sensitivity to targeted therapies could offer significant clinical benefit. We report that 22% of the high grade OvCa tumors at diagnosis express CIP2A oncoprotein at low levels. CIP2Alow OvCa tumors have significantly lower likelihood of disease relapse after standard chemotherapy, but yet a portion of relapsed tumors retain their CIP2Alow phenotype. We further discover that reactive oxygen species (ROS) inducing compound APR-246 (PRIMA-1Met/Eprenetapopt), currently in clinical development, preferentially kill CIP2Alow OvCa cells across multiple chemotherapy resistant cell lines. Consistent with CIP2Alow OvCa subtype in humans, CIP2A is dispensable for development of MISIIR-TAg-driven mouse OvCa tumors. Nevertheless, CIP2A deficient OvCa tumor cells from MISIIR-TAg mice displayed APR-246 hypersensitivity both in vitro and in vivo. Mechanistically, the lack of CIP2A expression hypersensitizes the OvCa cells to APR-246 by inhibition of NF-kB activity. Accordingly, combination of APR-246 and Nf-kB inhibitor compounds strongly synergized in killing of CIP2A positive OvCa cells. Collectively, we discover low CIP2A expression as a vulnerability for APR-246 in OvCa. The results warrant consideration of clinical testing of APR-246 for CIP2Alow OvCa tumor subtype patients, and reveal CIP2A as a candidate APR-246 combination therapy target.

Despite saturated genetic profiling of breast cancers, oncogenic drivers for the clinically challenging basal-like breast cancer (BLBC) subtype are still poorly understood. Here, we demonstrate that CIP2A is selectively essential for DNA damage-induced initiation of mouse BLBC tumors, but not of other cancer types. Mechanistically, CIP2A was discovered genome-widely the closest functional homologue for DNA-damage proteins TopBP1, RHNO, POLQ, NBN and PARP1. CIP2A directly interacts with the ATR-activation domain of TopBP1, and dampens both, chromatin binding of TopBP1 and RAD51, and G2/M checkpoint in DNA-damaged cells. CIP2A also drives BLBC-associated proliferative MYC and E2F1 signaling. Consistently with high DNA-damage response activity BLBCs, and CIP2A’s novel role in checkpoint signaling, CIP2A was found essential for DNA-damaged, and BRCA-mutant BLBC cells. Selective role for CIP2A as BLBC driver was supported by association of high CIP2A expression with poor patient prognosis only in BLBC, but not in other breast cancer types. Therapeutically, small molecule reactivators of PP2A (SMAPs) phenocopy CIP2A-dependent DNA damage response, and inhibit in vivo growth of patient-derived BLBC xenograft. In summary, we discover sub-type selective essential role for CIP2A in BLBC initiation and maintenance that can be explained by its newly discovered association with DNA-damage response, coordinated with regulation of proliferative signaling. The results also identify therapeutic strategy for CIP2A-dependent BLBCs.

Chronic obstruction of the biliary system may cause hepatic fibrosis and liver failure. The purpose of this study was to define the incidence of unrecognized liver fibrosis in patients undergoing pancreaticoduodenectomy (PD). Retrospective data were collected on patients undergoing PD during a 21-month period. Each patient had a core needle biopsy at the time of surgery by a hepatobiliary surgeon. This study identified 36 consecutive patients who were referred to a tertiary center and underwent pancreatoduodenectomy during a period of 21 months. The majority of patients, 32 (88.8%), were diagnosed with pancreatic adenocarcinoma. Liver fibrosis was diagnosed in 23 (63.9%) patients. A total of 25 (69.4%) patients were found to have pathological evidence of cholestasis consistent with bile obstruction. Patients that were found to have evidence of obstruction had significantly increased odds that fibrosis stage 2 would be found on pathological diagnosis (OR 6.75, 95% CI 1.20–38.02, Fisher’s exact test P value = 0.0312). There was no significant association in patients who were stented compared to non-stented patients and their diagnosis of high-grade fibrosis stage 2 (OR 1.5238, 95% CI 0.4019–5.7769, Fisher’s exact test P value = 0.7360). An astonishing 63.9% of patients who underwent PD were diagnosed with stage 1–4 liver fibrosis and half (47.2%) had fibrosis stage of 2 or more. Further, stent status had no significant impact on the degree of liver fibrosis. Liver fibrosis is currently underrecognized in patients undergoing PD, which is important for physicians to be conscious of as it is known that liver fibrosis increases morbidity and mortality.

Hepatopancreatobiliary (HPB) surgery experience during residency in the Americas is limited. Residents interested in HPB surgery have different options available for further training. This study evaluated training in HPB surgery received during general surgery (GS) residency, and sought to determine the perception of fellowship training in HPB surgery.An anonymous survey was distributed to all 259 GS residency programs in the United States. Questions evaluated demographics, program structure, overall trainingHPB experience in particular during residency, plans for fellowship training and understanding of training in HPB surgery.Of the 340 respondents, 162 (48%) were from university programs, 145 (43%) from community hospitals and 48 (14%) from independent medical centers. 117 (34%) were residents in postgraduate year 4 or 5 (PGY4/PGY5). 275 (81%) respondents were planning to pursue fellowship training after finishing residency. Three quarters of all respondents did not feel comfortable about performing liver, biliary and pancreatic procedures. Fellowships accredited by the Americas Hepato-Pancreatico-Biliary Association (AHPBA) are the most common pathway considered by residents for HPB training.GS residents are not comfortable in considering performing complex HPB cases on completion of residency training. GS residents consider AHPBA accredited fellowships to be more suitable for advanced training in HPB surgery.

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is involved in immune response, cancer progression, and Alzheimer's disease. However, an understanding of the mechanistic basis of its function in this wide spectrum of physiological and pathological processes is limited due to its poorly characterized interaction networks. Here we present the first systematic characterization of the CIP2A interactome by affinity-purification mass spectrometry combined with validation by selected reaction monitoring targeted mass spectrometry (SRM-MS) analysis in T helper (Th) 17 (Th17) cells. In addition to the known regulatory subunits of protein phosphatase 2A (PP2A), the catalytic subunits of protein PP2A were found to be interacting with CIP2A. Furthermore, the regulatory (PPP1R18, and PPP1R12A) and catalytic (PPP1CA) subunits of phosphatase PP1 were identified among the top novel CIP2A interactors. Evaluation of the ontologies associated with the proteins in this interactome revealed that they were linked with RNA metabolic processing and splicing, protein traffic, cytoskeleton regulation and ubiquitin-mediated protein degradation processes. Taken together, this network of protein-protein interactions will be important for understanding and further exploring the biological processes and mechanisms regulated by CIP2A both in physiological and pathological conditions., Graphical abstract A schematic representation of the CIP2A interactome study: CIP2A immunoprecipitation (IP) was performed after 72 ​h of polarization of naïve T cells towards the Th17 lineage. Two CIP2A specific antibodies (Ab1 and Ab2), targeting the N-terminal structured region and unstructured C-terminus, were used together with their respective IgG (IgG1 and IgG2) control antibodies. Following LC-MS/MS analysis to identify the CIP2A associated proteins, statistical analysis using the Significance Analysis of INTeractome (SAINT) algorithm was used to distinguish non-specific interactions.Image 1, Highlights • The first characterisation of the CIP2A interactome in Th17 ​cells. • Key interactions validated by targeted SRM-MS proteomics, western blot and confocal microscopy. • Pathway analysis of the interactome revealed interrelationships with proteins across a broad range of cellular processes. • The study identifies for the first time the interaction of phosphatase PP1 with CIP2A.

This study aims to answer three very basic questions regarding the capital structure of firms by testing the predictions made by the trade-off theory of capital structure. It employs a variety of data specification to test the relationship of financial leverage with profits, growth and firm size and takes help from existing literature for and against the trade-off model. It aims at testing the relatively aged literature, which widely disregarded the trade-off model with later studies that suggested that adequate data structure does report this theory to be empirically valid. The variety of specifications of data does lead the author to the general result that although most of the predictions of the trade-off model hold true empirically, the results of estimation on profits and leverage still hold that the model only had limited validity empirically.

Sharpin, a multifunctional adaptor protein, regulates several signalling pathways. For example, Sharpin enhances signal-induced NF-κB signalling as part of the linear ubiquitin assembly complex (LUBAC) and inhibits integrins, the T cell receptor, caspase 1 and PTEN. However, despite recent insights into Sharpin and LUBAC function, a systematic approach to identify the signalling pathways regulated by Sharpin has not been reported. Here, we present the first 'Sharpin interactome', which identifies a large number of novel potential Sharpin interactors in addition to several known ones. These data suggest that Sharpin and LUBAC might regulate a larger number of biological processes than previously identified, such as endosomal trafficking, RNA processing, metabolism and cytoskeleton regulation. Importantly, using the Sharpin interactome, we have identified a novel role for Sharpin in lamellipodium formation. We demonstrate that Sharpin interacts with Arp2/3, a protein complex that catalyses actin filament branching. We have identified the Arp2/3-binding site in Sharpin and demonstrate using a specific Arp2/3-binding deficient mutant that the Sharpin-Arp2/3 interaction promotes lamellipodium formation in a LUBAC-independent fashion.This article has an associated First Person interview with the first author of the paper.

Two complimentary routes to chiral dibenzazepinium halides have been developed. This has enabled the synthesis and evaluation of a range of potential phase-transfer catalysts (PTC) for asymmetric alkylation and Michael addition reactions involving glycine imine esters.

This paper examines earnings management activities around debt covenant violations. We focus on accruals management and real activities manipulation behaviour of managers in the quarters around the covenant violation. We expect covenant restrictions to influence these activities in the quarters surrounding and the quarter of the violation. The evidence is consistent with managers manipulating earnings using accrual-based and real earnings management activities and provides evidence for the debt covenant hypothesis. Cross-sectional analyses reveal that managers appear to manipulate accruals in successive quarters in order to increase reported earnings. The evidence on the use of real activities suggests that while managers increase reported earnings in the violation quarter, they have limited discretion over the use of real earnings management techniques in the quarters surrounding the violation.

A short synthetic route to diastereoisomeric atropos dihydro-5H-dibenz[c,e]azepinium salts via reaction of a single enantiomer of (R)-α-methylbenzylamine with a racemic atropos biphenol derivative is described. Compounds prepared via this approach are used to provide strong evidence that structurally related tropos dihydro-5H-dibenz[c,e]azepinium salts preferentially react via a single conformation in PTC reactions involving glycine imine enolates.