Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin-Goltz syndrome or Gorlin syndrome, is a rare multisystem disorder with an estimated prevalence of around 1 in 100,000 on average. Vismodegib, an oral smoothened (SMO) inhibitor that blocks the activation of the sonic hedgehog (SHH) pathway, is used in patients with NBCCS. We present an interesting case of a 38-year-old female with Gorlin-Goltz syndrome and her response to vismodegib therapy over two and a half years. She had an excellent initial response to vismodegib for a year during which all her skin basal cell carcinoma (BCC) lesions decreased in size considerably; her dentigerous cysts remained the same size. Though she continued therapy despite several side effects, this was only followed by tumor regrowth and the emergence of new BCC lesions in a more aggressive manner. We discussed the proposed mechanism of resistance to vismodegib (based on our case and literature review) along with its clinical implications. Our case highlights that vismodegib resistance might lead to progression of Gorlin syndrome to a more aggressive version, and points out the need to determine the optimal regimen (combining vismodegib with other agents) and optimal therapy duration (continuous treatment vs. discontinuation after best response) for treatment of NBCCS. Nevoid basal cell carcinoma syndrome (NBCCS) also known as Gorlin-Goltz syndrome or Gorlin syndrome is a rare, autosomal dominant, multisystem disorder with an estimated prevalence of around 1 in 100,000 on average . It is cNBCCS is diagnosed clinically with two major criteria (or) one major and two minor criteria . Major cVismodegib, an oral smoothened (SMO) inhibitor that blocks the activation of the sonic hedgehog (SHH) pathway, approved for the treatment of advanced and metastatic BCC, has been used in patients with NBCCS. In a randomized trial, vismodegib has been shown to decrease the tumor burden of BCC in patients with NBCCS, and nearly 54% of patients experienced severe side effects like muscle cramps, hair loss, ageusia and weight loss leading to treatment discontinuation . Due to We present an interesting case of a 38-year-old female with Gorlin-Goltz syndrome and her long-term response to vismodegib therapy. She was able to tolerate vismodegib therapy despite its side effects, had an excellent initial response to the drug for about a year followed by tumor regrowth. We also discussed the proposed mechanism of resistance to vismodegib and its potential clinical implications (based on our case and literature review).A 38-year-old female with a past medical history of spina bifida, jaw cyst excision at the age of 8, and multiple BCC treated with either excision or electrodesiccation and curettage (ED & C) at the age of 25 presented with multiple skin lesions on the scalp, face and the neck. Biopsy of three of those (most prominent) lesions revealed BCC and was treated with ED&C. Further diagnostic workup included CT head which showed calcifications of tentorium and falx cerebelli with bridging of sella turcica; CT maxillofacial & neck which showed two posterior maxillary  unilocular cysts consistent with odontogenic keratocysts; chest X-ray which showed no rib abnormalities, and a pelvic ultrasound which showed no ovarian fibromas Figures -3.Gorlin syndrome was diagnosed using diagnostic criteria . She hadEleven months after vismodegib initiation, she started having an increase in the size of the existing lesions along with new skin lesions in the following pattern. Over the following six months, she had three new BCC lesions - one each on the right temple, the right shoulder, and the left eyelid which continued to grow extensively into the supraorbital ridge and lateral rectus muscle despite debulking. Over the subsequent next nine months, she had 11 new BCC lesions - two BCCs on the left shoulder, one on the right cheek, two BCCs on the right lateral eyebrow/right temporal area, four BCCs on the upper back, lower back, right temple, right temporal hairline, one on left jaw and one on right forehead. Over the next three months, she developed seven new BCC lesions on the right frontal scalp, left frontal scalp, right superior temple, right lateral eyebrow, left neck in the postauricular area. Some of her facial lesions were treated with Mohs surgery, and all the remaining lesions were treated with ED&C.Throughout these two and half years of vismodegib therapy, she had nausea, dysgeusia , grade I diarrhea, bilateral lower extremity cramps, hair loss, amenorrhea as side effects which were not severe enough to warrant discontinuation of therapy. Finally, after 2.5 years of vismodegib therapy, vismodegib was discontinued due to unclear benefit, recurrence of BCC which occurred with an increased frequency as time progressed, and persistent side effects which did not improve with time.This is an interesting case of Gorlin-Goltz syndrome where i) the skin lesions  had an excellent and durable response to vismodegib, for almost a year, followed by regrowth of old lesions and the emergence of new lesions implying the development of resistance to vismodegib, ii) the new BCC lesions developed with increased frequency as time progressed despite continued therapy suggesting that the mutations/mechanisms causing vismodegib resistance might be responsible for the development of aggressive version of Gorlin syndrome, iii) the bilateral keratocysts/dentigerous cysts showed no response to the drug implying vismodegib is not an optimal treatment option for keratocysts, and iv) she had many side effects (the leading cause of drug discontinuation in most cases) from vismodegib but were not distressing enough to warrant discontinuation and the side effects did not improve with time.Below is a brief review of the pathogenesis of NBCCS to understand the proposed mechanisms for the development of vismodegib resistance and its clinical implications. As discussed in the introduction part, overactivation of the sonic hedgehog (HH) signaling pathway is responsible for the development of BCC and other tumors .Normal hedgehog pathway (after embryonic development)The secreted hedgehog proteins act on the transmembrane receptor complex formed by two proteins-patched (PTCH) and smoothened (SMO). Smoothened (SMO) activation results in intracellular signal transduction leading to downstream activation of Gli nuclear transcription factors, which ultimately regulates hedgehog target gene expression causing cellular proliferation -9. When Abnormal hedgehog pathway in NBCCSInactivating mutations of either patched (PTCH) or suppressor of fused (SUFU) genes lead to loss of inhibition of smoothened (SMO) and Gli nuclear transcription factors, respectively, leading to excess hedgehog (HH) target gene expression and thereby, excess cellular proliferation resulting in development of cancer Figure  5,8].,8.5,8].Vismodegib resistanceIn a study of 28 patients (including five patients with NBCCS), tumor regrowth during treatment with vismodegib occurred in six patients (21%) with a mean time to regrowth of 56 weeks -15. The Additional studies are needed to determine the optimal regimen, i.e., combining vismodegib with agents that inhibit smoothened (SMO) through different receptor or agents that inhibit hedgehog (HH) pathway downstream of smoothened (SMO). Additional studies are necessary to determine the optimal duration of vismodegib therapy, continuous treatment vs. discontinuation after best response, to prevent the development resistance to vismodegib. Further studies are required to determine if the development of resistance to vismodegib has any implications in the progression of Gorlin syndrome to a more aggressive version.


W) algorithm. In this approach, the normal samples being completely and exclusively clustered into one class is considered to be the standard of reasonable clustering subtypes, and the feature selection pays attention to imbalances of samples among subtypes. With this approach, we identified the molecular subtypes of colon cancer on the mRNA gene expression dataset of 153 colon cancer samples and 19 normal control samples of the Cancer Genome Atlas (TCGA) project. The colon cancer was clustered into 7 subtypes with 44 feature genes. Our approach could identify finer subtypes of colon cancer with fewer feature genes than the other two recent studies and exhibits a generic methodology that might be applied to identify the subtypes of other cancers.Identifying molecular subtypes of colorectal cancer (CRC) may allow for more rational, patient-specific treatment. Various studies have identified molecular subtypes for CRC using gene expression data, but they are inconsistent and further research is necessary. From a methodological point of view, a progressive approach is needed to identify molecular subtypes in human colon cancer using gene expression data. We propose an approach to identify the molecular subtypes of colon cancer that integrates denoising by the Bayesian robust principal component analysis (BRPCA) algorithm, hierarchical clustering by the directed bubble hierarchical tree (DBHT) algorithm, and feature gene selection by an improved differential evolution based feature selection method (DEFS Identifying the molecular subtypes of colorectal cancer (CRC) may allow for more rational, patient-specific treatment in the future. Various studies have been done to predict molecular subtypes for CRC based on gene expression data. Fearon and Vogelstein utilized four different genomic and epigenomic instabilities to identify four subtypes of CRC: chromosome instability (CIN), microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and DNA global hypomethylation . Using cW) method [W algorithm. In view of the usual imbalance of samples among subtypes, we use the naive Bayes (NB) classifier with empirical prior probabilities and weight accuracy to evaluate classification ability. The empirical prior probabilities estimate the prior probabilities from the relative frequencies of the classes in training, which can lessen the influence of the imbalance of samples. Weight accuracy is a special assessment measurement for classification of imbalance samples.One popular approach to identifying cancer subtypes is clustering the gene expression data of patient samples, as expression data can give a comprehensive snapshot of transcription activities for whole genomes . Because) method , which nW. We applied this approach to the Cancer Genome Atlas  mRNA gene expression dataset of colon cancer and identified 7 subtypes with 44 feature genes. The results deliver finer subtyping with fewer feature genes than in the other two recent studies.In this study, we integrated these state-of-the-art techniques of denoising, clustering, and feature selection to identify molecular subtypes in human colon cancer using gene expression data. Our integrated approach incorporates denoising by the BRPCA, hierarchical clustering by the DBHT, and selecting feature genes by DEFSThe microarray mRNA gene expression dataset we used to identify the subtypes of colon cancer is from TCGA. It includes 153 cancers samples, which have been used by Muzny et al.  and Ren W to select the feature genes for the clusters. A summary of our approach is shown in We first applied the BRPCA to denoise the gene expression data by getting the sparse component but removing the low-rank and noise components, and then we used the DBHT to cluster the sparse components in the BRPCA. The normal samples completely and exclusively clustered into one class were considered as the standard of reasonable clustering. If the standard was not reached, we continually tuned the setting of the hyperparameters of the BRPCA until the clustering was up to the standard. Finally, we used the DEFSIn the BRPCA model , the obsIn our study, the observed data matrix For Since the density function at one layer is conjugate to the density function at the layer above it, the posterior density function is easily computed via Markov chain Monte Carlo (MCMC) implemented using a Gibbs sampler. The details for calculation of the BRPCA algorithm are described in algorithm 1 in Ding et al. .The directed bubble hierarchical tree (DBHT)  algorithIn our study, a sample is a vertex and the Pearson’s correlation coefficient matrix is used as the similarity matrix of the vertexes.The dissimilarity matrix of the vertexes we used is:Based on the similarity and dissimilarity matrix of samples, the DBHT constructs the PMFG to perform clustering and get hierarchies of samples. The details for the DBHT algorithm are described in Song et al. .O [W [O, the desired feature subset size is predefined by the user, while in the DEFSW, the optimal feature subset size can be discovered automatically only by setting an upper limit. In the two algorithms, a wrapper classifier such as K nearest neighbor (KNN), support vector machine (SVM), or naive Bayes (NB) classifier is needed. The wrapper classifier and an assessment measurement such as classification accuracy are used together to evaluate the classification ability of features.To identify the subtypes using gene expression profiling, feature selection can be used to reduce the high-dimensionality of huge amounts of otherwise meaningless data. Khushaba and Al-Ani et al. proposed a powerful feature selection method that utilizes the differential evolution (DE) float number optimizer in the combinatorial optimization problem of feature selection, named DEFSO , followeO [W . In the W algorithm and its parameter setting that we used are listed in In our study, some subtypes have a small number of samples and others have a lot, i.e., there are imbalances of samples among subtypes. Therefore, a wrapper classifier and an assessment measurement that can cope with the class imbalance have to be used to avoid the “larger subtypes win.” Meanwhile, for the DE algorithm, the computation cost is generally huge because of its iterative evolution, so a fast and simple classifier is desired. Not only can the NB classifier be trained very efficiently under the condition of a small amount of training data and take only linear time, but its empirical prior probabilities can lessen the influence of the imbalance of samples. To assess classification ability, we used weight accuracy instead of the usual classification accuracy. The weight accuracy of classification is defined by Draminski et al.  as:(13)wWe first used the BRPCA to denoise. In the BRPCA model, we set the largest possible rank as ters see , in whicWe also tried to directly cluster the mRNA gene expression dataset using DBHT without denoising . It sugge result b suggestw algorithm. Considering that the latent premise of identifying subtypes is that the samples are from cancer patients, we expected that the selected feature genes could not only identify cancer subtypes, but also discriminate between tumor and normal samples, i.e., we expected to select out the feature genes that could discriminate all eight sample clusters. It was rational to select the feature genes from the differentially expressed genes (DEGs) of tumor vs. normal samples. We obtained 5897 DEGs by t-test  and fold change cutoff 1.5, and then selected the feature genes from these DEGs using the DEFSW algorithm described in w algorithm could deliver an optimal size of feature genes. We then determined our final size of feature genes to be that which gave the maximal average weight accuracy of the eight sample clusters. In this way, we ended up with 44 feature genes: THBS2, NOX4, KIAA1199, SLC16A4, CCDC19, ZNRF3, GOLT1A, HYAL3, C15orf26, KIFC1, TIPIN, CTNNAL1, CALU, TAF1A, MCM2, MSH6, FLAD1, GCG, SCRG1, PTGER2, TIMD4, MUC1, PLOD2, LIMS2, ADH1B, PTN, PTPN7, AQP1, PSD3, CRAT, ATOH8, CGN, C6orf204, FTHP1, KCNMB1, LIG4, PPFIBP2, PPP2CB, ALAS2, ZZEF1, ATXN7, GRLF1, FAM102A, and C1orf152. Among them, MSH6 is known to be related to CRC, and is located in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway of CRC [THBS2 is a potential prognostic biomarker in CRC [NOX4 predicts poor prognosis and promotes tumor progression in human CRC [NOX4 plays a role in PhIP-induced colon carcinogenesis, especially during the early stages before tumor onset [NOX4 is highly predictive of relapse in stage II left-side colon cancer [KIAA1199 in human colorectal tumors  is markedly higher than that in the normal colonic mucosa [KIAA1199 plays a critical role in maintaining an aggressive phenotype of tumor cells, and suppression of KIAA1199-related motilities of tumor cells contributes to reduced tumor metastasis in CRC [MCM2 is correlated with the cell proliferation state in colon cancer [Ki-67 in identifying colorectal mucosal proliferation [MUC1 is aberrantly overexpressed in human colon cancers and is associated with invasion, metastases and a poor prognosis [ZNRF3 is important in serrated tumorigenesis and has identified a potential therapeutic strategy for CRC subtype [LIG4 may represent a new epigenetic marker for CRC independent of known markers [ADH1B displays decreased expression during progression from adenoma to early and more advanced stage of colorectal carcinomas [We then selected the feature genes for the identified subtypes by the DEFSr in CRC  and can r in CRC ; Overexpuman CRC , and NOXor onset , and morn cancer ; KIAA119c mucosa ,33 and ic mucosa , and couc mucosa ; Furthers in CRC ; MCM2 isn cancer  and is mferation ; MUC1 isrognosis ,40; ZNRF subtype ; LIG4 ma markers ; ADH1B drcinomas . In contWe used the same NB classifier to validate the classification ability of these feature genes. We did 10%, 20%, and 30% cross-validation (CV) with 1000 repeats. The mean classification accuracy, the mean weight accuracy of classification, and the mean classification accuracy for each class of the 1000 CVs are listed in w algorithm can discover the optimal feature subset size. Considering the unstable stochastic search, we repeated the DEFSw algorithm multiple times with different upper limits of the feature size and selected the feature genes from the DEGs. This may be helpful for selecting out the optimal size of feature genes and getting higher accuracy for discriminating tumor and normal samples. Overall, the proposed approach can identify finer subtypes of colon cancer with fewer feature genes than the other two recent studies and exhibits a generic methodology for identifying cancer subtypes based on gene expression data by common processes.To identify cancer subtypes based on gene expression data, the proposed approach innovatively integrated state-of-art denoising, clustering, and feature selection algorithms. In BRPCA, the low-rank component of gene expression data may be the same as the background of an image and the noise component simulates unknown and nonstationary noise, whereas the sparse component may be the same as the foreground and is the key information for clustering. The DBHT is intrinsically a correlation-based clustering method. Through building the PMFG, the method does not need any prior tuning and provides both intracluster hierarchy, which describes the way clusters are composed, and intercluster hierarchy, which describes how clusters gather together. To assess whether the clustering is meaningful, we draw in the concept of “reference object” from classical physics. If the reference objects, the normal samples, are correctly clustered together, we consider the clustering as reasonable; otherwise, we need to tune the parameters in the BRPCA. Tuning the parameters means adjusting the degree of details of component Inter-tumor diversity of CRC complicates the prediction of disease and treatment outcomes. Subtypes of colorectal cancer identified by classifying gene expression profiles with defined prognostic markers would predict individual patient outcomes more precisely and therefore provide valuable guidance on appropriate therapeutic intervention . It is p


Traumatic brain injury (TBI) resulting from forceful impacts on the torso and head has been of major interest because of the prevalence of such injuries in military personnel, contact sports and the elderly. Cognitive and behavioral changes associated with TBI are also seen following whole brain radiation treatment for cancer and chemotherapy for disseminated tumors. The biological mechanisms involved in the initiation of TBI from impact, radiation, and chemotherapy to loss of cognitive function have several shared characteristics including increases in blood brain barrier permeability, blood vessel density, increases in inflammatory and autoimmune responses, alterations in NMDA and glutamate receptor levels and release of proteins normally sequestered in the brain into the blood and spinal fluid. The development of therapeutic agents that mitigate the loss of cognition and development of behavioral disorders in patients experiencing radiation-induced injury may provide benefit to those with TBI when similar processes are involved on a cellular or molecular level. Increased collaborative efforts between the radiation oncology and the neurology and psychiatry communities may be of major benefit for the management of brain injury from varied environmental insults. Radiation treatment to the brain (for management of neoplasms) and non-penetrating traumatic brain injury (TBI) are clinical conditions that result in major changes in neural function. While the majority of traumatic brain injuries (TBI’s) are associated with falls, and vehicular accidents, this paper will have a focus on TBIs resulting from the forceful impacts of sports or military activities . DecremeIn the field of neuro-oncology, radiation therapy is an effective therapeutic treatment for neoplasms across ages and cancer subtypes with the consequence of cognitive decline dependent on the age of the patient, the volume of brain irradiated and the dose delivered ,22,23,24While cognitive decline secondary to radiation therapy is a problem that continues to be studied, understanding and solving this problem is difficult for several reasons: (1) wide variations in age, treatment technique, tumor types, and cognitive performance scoring make generalizations difficult, (2) most patients are not cured and thus competing sources of cognitive decline such as tumor progression and further chemotherapy confound most analyses, and (3) radiation oncologists are increasingly utilizing the technique of stereotactic radiosurgery (SRS) over whole brain radiotherapy (WBRT) which minimizes dose to the healthy brain, thus limiting the pool of patients that would be best for studying cognitive decline ,40,41,42Radiation to the brain is administered in one of two treatment paradigms: (1) 5–30 treatments, each delivering a dose of 1.5–4 Gy, to a relatively wide area that encompasses normal brain, or (2) 1–5 treatments, each delivering a dose of 5–24 Gy, with minimal normal brain contained within the high dose field ,44,45,46WBRT has global effects on the brain with measurable deficits in energy, episodic verbal learning, verbal fluency, processing speed, visual attention, task switching, and memory ,3. To esKondziolka et al. measured the quality of life of patients who had 2–4 brain metastases and received SRS +/− WBRT (30 Gy divided into 12 daily treatments) . They foSimilar to patients who receive WBRT, patients who experience TBI report deficits in memory, attention, awareness, judgement, language, visuospatial processing, and general intelligence ,6,7,8,52The localization of these deficits in TBI patients can help radiation oncologists predict the expected side effects from radiotherapy and provide potential areas to shield from radiation. For example, Spikman et al. found that patients who have imaging-confirmed frontal lobe changes frequently have deficits in self-awareness and have impaired self-evaluative ability . NewcombIn patients who have multiple brain lesions and receive WBRT, their cognitive function declines steadily over the course of months to years ,3,54,55.Our group’s hypothesis regarding the effect of WBRT on brain injury is that there are two processes, acute and delayed, that have differing time courses and cognitive effects. When the entirety of a healthy adult brain is exposed to radiation, the patient will suffer acute declines in processing speed and alertness within 1–6 months that are the result of direct damage on neuronal stem cells. However, in the absence of tumor progression, a proportion of these patients will recover from these acute effects. At the same time, a subset of patients will experience delayed effects from radiotherapy that result from the subtler changes in the brain that result from receptor level changes and chronic neuroinflammation. Patients that receive higher radiation doses to the whole brain appear far more likely to suffer from these delayed cognitive deficits.Somewhat similarly to the acute effects of WBRT, impairment from TBI is worst at the time of the incident and patients typically improve over months before reaching a plateau within a year . In patiWhile the time courses of radiation-induced and trauma-induced cognitive decline are not congruent, it does give us clues on the speed at which the brain heals itself and on the cumulative effects of chronic inflammation.Trauma and radiation therapy both preferentially damage certain regions of the brain. Radiation appears to have preferential effects on the para-hippocampal cingulum, cuneate cortex, prefrontal cortex, cerebellum, and thalamus . CliniciInitial human trials have focused on decreasing the dose to the hippocampus as much as possible rather than squelching the inflammatory effects. Gondi et al. demonstrated in their phase II trial that keeping the hippocampal dose below 9 Gy (given over 10 treatments) resulted in less decline in the Hopkins Verbal Learning Test (HVLT) versus historical controls (7% versus 30% at 4 months) . The ongIn the case of TBI, the primary sites of injury are traditionally characterized as being greatest at the base of the sulci near the site of impact (the coup) and the area of the brain opposite this region (the contre-coup) . More reBoth trauma and ionizing radiation temporarily disrupt the permeability of the blood-brain-barrier ,75,76,77Radiation induces increased levels of neuronal biomarkers in the CSF and bloodstream like neurofilament light protein (NFL), and T-tau but NFL release is thought to be independent of blood-brain barrier permeability ,79. WorkIn the long term, radiation appears to reduce both blood vessel density and blood vessel length in the brain which likely plays a large role in the long-term detrimental effects of radiotherapy. Brown et al. irradiated young-adult rats with fractionated WBRT (40 Gy in 8 treatments over 5 weeks) and dissected their brains at several time points over a year . They foWhen fetal mouse neuronal stem cells are exposed to radiation in-vitro, they undergo an alternate differentiation pathway that results in neurons with a higher expression of glutamate receptors . In younWhen adult rats were exposed to cranial irradiation, their NMDA receptors on their hippocampal neurons showed additional NR1 and NR2A subtypes compared to non-irradiated controls but their AMPA receptors levels were unchanged . In a seReceptor level changes in cannabinoid, benzodiazepine, aquaporin 4, vimentin, NMDA, AMPA, and GABA receptors have been recorded after TBI in rodent models ,91,92,93Both radiation and trauma cause neuroinflammation in both the acute and chronic settings. In the setting of radiation, the acute neuroinflammation seen after radiation is more immediate and likely attributable to proinflammatory cytokines directly secreted by damaged neurons and microglia .After C57BL/6 mice were irradiated with a single-dose of cranial irradiation between 0–35 Gy, transcript levels of inflammatory cytokines were elevated and glial and endothelial cells were activated . When thOther drugs with therapeutic potential are the peroxisome proliferator-activated receptor (PPAR) agonists which regulate inflammatory signaling . When F3The same enthusiasm for mediating neuroinflammation exists in the TBI research community and dozens of pre-clinical experiments have shown significant reductions in TBI when anti-inflammatories are given immediately after injury . One theThough the CRASH trial had negative results in TBI patients, glucocorticoid use in cranial radiotherapy patients has tremendous potential as glucocorticoids reduce the vasogenic edema commonly associated with larger tumors and reduce intracranial pressure . Almost There are some similarities between the symptoms, pathological processes and cellular level changes that occur after either radiation or forceful impact trauma to the brain which gives hope that therapeutic targets that are effective for one may be applied to the other. The potential role of autoimmune processes, as components of the mechanism resulting in cognitive and behavioral loss following exposure to radiation or forceful impacts, may enable the development of pharmaceutical or other treatments to mitigate these injuries.


To tolerate and recover from genotoxic stress cells must coordinate a range of stress response activities including cell cycle arrest, DNA repair, and remodeling of the transcriptome and proteome. The suppression of ribosome production is a key feature of many stress responses in yeast, and much is known about the dynamics of this process at the transcriptional level. In our recent study, (J Cell Biol doi: 10.1083/ jcb.201612018) we focus on the stress related dynamic behaviour of a splicing factor called Hsh155, which is a core component of the SF3B subcomplex of the U2 small nuclear ribonucleoprotein complex, homologous to human SF3B1. The disassembly from its complex and sequestration of Hsh155 into nuclear protein aggregates contributes to suppressing ribosome production post-transcriptionally by promoting intron retention in ribosomal protein gene transcripts. The relocalization of Hsh155 is facilitated by TORC1-driven transcriptional changes and molecular chaperones that recognize disassembled Hsh155, eventually aiding in efficient recovery from stress. Protein quality control (PQC) is an essential part of cellular homeostasis and encompasses the balance of non-native protein folding and degradation. Under stress, triage of non-native or disassembled proteins to aggregate structures mitigates cellular damage and allows cells time to either degrade or reactivate aggregated proteins upon stress recovery. We identified Hsh155 in a screen for GFP-fused proteins that moves after treatment of yeast cells with methyl methanesulfonate, hydrogen peroxide or ultraviolet light. Hsh155 moves into foci after MMS treatment and disassembles from its partners Hsh49 and Cus1 in the SF3B complex. This indicated to us that Hsh155 becomes non-native after stress. Accordingly, we found that it localized with markers of a recently identified nuclear PQC compartment called the intranuclear quality control (INQ) compartment. We tested the dynamics of Hsh155 in its aggregated form and found a shift of aggregate accumulation from INQ to cytoplasm over time, leading to a younger pool in the cytoplasm. As with other PQC localized proteins, Hsh155 sequestration is promoted by the aggregases Btn2 and Hsp42, and counteracted by disaggregases like Hsp104. Loss of Hsh155 function or loss of the aggregase Btn2 impaired the recovery of cells from MMS treatment upon stress removal. Interestingly, Hsh155 localization was not influenced by loss of the canonical DNA damage signaling kinases Tel1 and Mec1, the yeast orthologues of human ATM and ATR, suggesting that other signals were likely stimulating the disassembly and aggregation of Hsh155.btn2Δ cells failed to increase intron retention in MMS. Together with our data showing that Btn2 is important for efficient stress recovery, this suggests that post-transcriptional shutdown of splicing may be a regulat-ed part of the stress response, which enforces suppression of RPG expression coupled with Hsh155 sequestration during stress.Whole proteome analysis of MMS treated cells confirmed suppression of ribosomal protein production, which had previously been seen as a major feature of transcriptional level change under different stresses. In yeast, ribosomal protein genes (RPGs) encode the vast majority of spliced transcripts due to the preponderance of introns in RPGs and their high expression levels. Thus, a shut-down of RPG transcription would dramatically reduce the need for splicing flux during stress. We observed the expected suppression of RPG expression after MMS treatment but saw a dramatic spike in intron-retention of RPG transcripts, suggesting that splicing was specifically inhibited. Remarkably, this splicing inhibition was dependent on the aggregase Btn2, as SFP1 gene completely blocked Hsh155 localization to INQ in MMS. Thus, we created a model in which stress signaling through TORC1, leads to the eviction of Sfp1 from RPGs, their transcriptional repression and liberation of spliceosomes from chromatin. The SF3B complex then disassembles and Hsh155 is sequestered by molecular chaperones at INQ until stress subsides .Finally, we wondered whether transcriptional repression was a pre-requisite to Hsh155 disassembly and relocalization to INQ. It was previously known that TORC1 signaling is important to control the dynamic responses of RPGs to stress through a transcription factor called Sfp1. Sfp1 rapidly relocalizes to the cytoplasm in a TORC1-dependent manner under stress, and this facilitates the precipitous drop in RPG expression. Accordingly, we found that treatment of cells with the TORC1 inhibitor rapamycin or genetic perturbations of TORC1 pathway components suppressed Hsh155 movement to INQ. Indeed, deletion of the Interestingly, two other INQ substrates, Cmr1 and Hos2, are known to bind to RPG promoters and are proposed as transcriptional regulators. Thus, a bigger picture emerges in which eviction of several proteins from chromatin due to transcriptional remodeling under stress may require protein aggregate sequestration for optimal stress tolerance. The potential for regulated coordination of transcriptome remodeling with protein sequestration in aggregates is one of the most exciting phenomena suggested by our work.One of the most obvious unanswered questions is why Hsh155, and no other proteins from the SF3B complex or the spliceosome relocalize to the INQ. What is special about Hsh155, Cmr1, Hos2 and other INQ resident proteins that makes them susceptible to genotoxic stress and why are they sequestered by the cell, rather than degraded? Careful analysis of INQ composition under different conditions should help to elucidate the common features of INQ substrate proteins under stress and may give insight to the signals driving their aggregation. Our work also sheds light towards broader questions about the nature and conservation of nuclear PQC. INQ forms adjacent to the nucleolus but what nuclear landmarks might dictate this positioning at the molecular level are unknown. Cells must coordinate the suppression of ribosomal RNA (rRNA) and RPG transcripts and it is tempting to speculate, based on the proximity of INQ to the nucleolus, that there may be some influence of INQ formation on rRNA biogenesis. Finally, potential links to human nuclear PQC are currently unclear. Human cells in culture do sequester proteins in the nucleolus under stress, providing a potential link to INQ behaviour that merits future study. Together, future studies looking at the molecular composition of INQ, how specific substrates are recruited, and how INQ composition determines global cell stress tolerance and survival, should reveal significant new insights to transcriptome dynamics in the stress response.


Monoclonal antibodies are utilized in clinical practice for the treatment of various diseases including cancer, autoimmunity, metabolic and infectious diseases. Over the last 20 years monoclonal antibodies have established themselves as therapeutics and various so-called “blockbuster” drugs are in fact antibodies. Currently ca. 80 monoclonal antibodies have been approved in Europe and the US and several hundreds of them are currently in early and advanced clinical trials. Notably, the field has significantly advanced in the last decade, and nowadays, a large proportion of antibodies in development are engineered antibodies including bispecific antibodies, antibody drug conjugates and novel antibody-like scaffolds. This Special Issue on “Monoclonal Antibodies” includes original manuscripts and reviews covering various aspects related to the discovery, analytical characterization, manufacturing and development of therapeutic and engineered antibodies.The collection starts with a number of reviews. Cho and colleagues  review tA series of original articles describes novel monoclonal antibodies for potential diagnostic or therapeutic application. Rashidian and colleagues describe a novel rabbit monoclonal antibody MRQ-67 that specifically recognize the R132H mutation of isocitrate dehydrogenase 1 (IDH1) which are prevalent in diffuse astrocytomas, oligodendrogliomas, and secondary glioblastomas but not the wildtype IDH1. MRQ-67 is able to identify neoplastic cells in glioma tissue specimens and can be used as a tool in glioma subtyping . Zhang aIn a series of three articles, Strube and colleagues ,8,9 descLastly, two articles deal with engineering monoclonal and bispecific antibodies. Tam and colleagues  have ideThis collection of articles should be of value to readers working in the field of monoclonal and therapeutic antibodies.


Patients infected with the hepatitis C virus (HCV) who drink heavily are likely to suffer more severe liver injury, promoting disease progression to cirrhosis and increasing their risk for liver cancer. Some research, although not conclusive, suggests that even moderate drinking may spur liver damage in HCV-infected patients. Research areas that have the greatest potential for developing more effective treatment options include HCV virology, immunology, animal models, and the mechanisms of liver injury. Hepatitis C is an infectious liver disease caused by the hepatitis C virus (HCV). The virus, which causes inflammation in the liver and can lead to more serious illness, primarily is spread by intravenous contact with the blood of an infected person. About 4 million people in the United States have been infected, making it the Nation’s most common blood-borne disease, resulting in the deaths of between 10,000 and 12,000 people each year . Those aThis article discusses the mechanisms by which alcohol may exacerbate HCV-infected patients’ risk of disease progression, reviews issues in the treatment of alcoholic patients with HCV infection, and addresses important areas of future research.Almost one-third of alcoholics with clinical symptoms of liver disease have been infected with HCV, which is four times the rate of HCV infection found in alcoholics who do not have liver disease . As showSeveral studies have indicated that heavy alcohol consumption accelerates patients’ progression from chronic HCV to cirrhosis , and liver cancer . Although fewer studies have examined the effects of moderate drinking on the course of liver disease in HCV patients, there is some indication that alcohol consumption in the moderate-to-heavy range may increase HCV-infected patients’ risk of developing liver fibrosis and cirrhosis. Research on whether gender has any effect on alcohol consumption and liver disease progression in HCV patients is very limited.In a study of 2,235 HCV-infected patients, Perhaps the most dramatic demonstration that alcohol multiplies HCV-infected patients’ risk of cirrhosis came from a study by People infected with both HCV and HIV are more likely to develop cirrhosis than are patients who are infected only with HCV, and alcoholism further potentiates this mechanism ., whereas those who drank less than 46 g per day were diagnosed with cancer an average of 31 years after transfusion. And An Italian survey showed that alcohol intake doubles the risk of hepatocellular carcinoma in HCV-infected patients who drink 41 to 80 g of alcohol per day (between 3.4 and 6.7 drinks) and quadruples the risk for patients who drink more than 80 g of alcohol per day . Other rMost studies have evaluated the effect of extremely heavy drinking on the progression of HCV infection to other liver disease, with little emphasis on the effects of moderate drinking on disease progression. However, some studies have found indications that moderate-to-heavy alcohol consumption also may increase the risk of developing liver fibrosis and cirrhosis in patients infected with HCV.Several other studies have examined the effects of moderate drinking on HCV progression.The data regarding the contribution of gender to the progression of HCV in alcoholics is quite limited. Chronic hepatitis C often is milder in women than in men, but women may be more sensitive than men to the adverse effects of alcohol .As discussed above, there is strong evidence that heavy alcohol consumption—and perhaps even moderate consumption—increases the risk that HCV infection will progress to more serious liver disease. In patients infected with HCV, alcohol consumption has a direct effect on liver histology. Specifically, patients with HCV who are drinkers show greater liver necrosis, inflammation, fibrosis, and fatty infiltration than HCV patients who do not drink. Further, alcohol consumption and fatty liver have been shown to act together to increase fibrosis in patients infected with HCV, especially in those who are obese and diabetic .Although researchers do not fully understand how alcohol consumption accelerates liver injury in patients with HCV infection, it is likely that several factors are involved. The following mechanisms have been proposed:Increased replication of HCV in the liver. As illustrated in Mutations of the HCV virus (forming what are known as quasi-species). Alcoholics infected with HCV show greater quasi-species complexity than do nonalcoholics with HCV infection. In alcoholic HCV patients, such increased viral complexity might make it difficult for the immune system to control the mutated viruses, leading to progressive injury .Increased programmed cell death (apoptosis) of liver cells. Apoptotic death of liver cells, which can ultimately lead to liver fibrosis, is increased by alcohol consumption in people with HCV infection .Higher levels of inflammation and immunoregulatory proteins . In research with mice, Viral gene mutations.Fatty liver. Accumulation of fat in the liver is common in patients with HCV. Examining a large group of patients with HCV infection, Accumulation of excess iron in body tissues . Alcohol consumption increases iron stores in the liver, and iron overload seems to contribute to HCV disease progression by inducing fibrosis .Alcohol Research & Health, .)Oxidative stress. Alcohol stimulates the production of reactive oxygen-containing molecules . Heavy alcohol use also depletes the body’s supply of molecules that normally defend tissues against damage caused by oxygen radicals . This state, known as oxidative stress, may accelerate liver damage in patients with HCV . , whereas some people may experience fatigue, weakness, fever, nausea, abdominal pain, poor appetite, muscle and joint pain, or yellowing of the skin and eyes (jaundice) . About 7Many patients who develop cirrhosis show no symptoms of the disease and can expect long-term survival . Data frTesting and TreatmentBlood tests can diagnose HCV infection, either by detecting antibodies to the virus or by detecting the presence and quantity of the virus’s genetic material (HCV RNA) itself . Liver bThere are six known genetic variants (genotypes) of HCV, which vary geographically in their rate of occurrence. Genotypes 1 (which accounts for 70 to 75 percent of cases), 2, and 3 constitute the majority of genotypes in the United States.The standard treatment for symptomatic hepatitis C infection is a combination of the drugs pegylated interferon (peginterferon) and ribavirin . Strict Currently, the best indicator of effective treatment is a sustained virological response (SVR), defined by the absence of detectable virus 24 weeks after the end of treatment. Early viral response  is predictive of SVR, and patients who fail to achieve an early viral response at week 12 should discontinue the treatment. Genotype 1 requires 1 year of treatment, whereas genotypes 2 and 3 require a 6-month course. In research with patients who did not consume alcohol during the therapy, SVR rates of 42 to 46 percent for genotype 1 and 76 to 82 percent for genotypes 2 and 3 have been obtained .— Eugene R. Schiff and Nuri OzdenCenters for Disease Control and PreventionRecommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic diseaseMorbidity and Mortality Weekly Reports471391998Di BisceglieAMNatural history of hepatitis C: Its impact on clinical managementHepatology3110141018200010733560Di BisceglieAMHoofnagleJHOptimal therapy of hepatitis CHepatology365 Suppl 1S121127200212407585FattovichGGiustinaGDegosFMorbidity and mortality in compensated cirrhosis type C: A retrospective follow-up study of 384 patientsGastroenterology11246347219979024300National Institutes of HealthNational Institutes of Health Consensus Development Conference statement: Management of hepatitis C: 2002—June 10–12, 2002Hepatology365 Suppl 1S320200212407572Some research has indicated that heavy drinkers who abstain from alcohol before interferon treatment respond better to treatment than do those who continue to drink. In one study, heavy drinkers who did not abstain from drinking before interferon treatment showed a total lack of HCV RNA clearance, whereas those who normally drank heavily but abstained from drinking before interferon treatment showed some improvement in HCV RNA clearance (and the virus completely disappeared in 15.8 percent of heavy drinkers who abstained before treatment) .However, this study indicated that when HCV-infected alcoholic patients who normally drank heavily  abstained from alcohol consumption during interferon therapy, their rate of HCV RNA clearance was markedly lower than was the case for HCV-infected nondrinkers see . These rThe evidence is strong that continued heavy alcohol intake during interferon treatment adversely affects treatment effectiveness. Further, depression, irritability, and anxiety—side effects that occur in 20 to 30 percent of patients who receive interferon treatment— may be especially difficult to manage for patients with a history of alcoholism, predisposing them to begin drinking again . DespiteA recent National Institute on Alcohol Abuse and Alcoholism conference  identifiDetermine how variations in the amount and pattern of drinking, combined drinking and smoking, and nutritional deficiencies affect HCV-infected patients’ risk of liver injury, disease progression, and death.Evaluate the effectiveness of alcohol cessation programs in patients with HCV.Specify how alcohol affects patients’ response to interferon treatment, including chemical interactions and day-to-day changes in virus activity during treatment.Determine how alcohol affects viral replication, clearance, and persistence and the evolution of new HCV quasi-species.Examine whether alcohol use leads to greater dominance of more harmful genetic variants of HCV.Determine whether alcohol interacts with the HCV viral proteins to alter the virus’s genetic activity.Identify the effects of alcohol on immune responses to HCV, including changes in quality, behavior, and survival of immune cell populations both within and outside the liver.Determine what factors activate the liver cells that deposit fibrous material at the site of injury and cause scarring . These factors may include the patient’s immune response to HCV infection, the specific HCV genotype, and oxidative stress triggered by alcohol use.Identify factors (including complementary medicines) that may inhibit stellate cell activation and fibrosis in HCV-infected patients who use alcohol.Clarify the roles that alcohol and HCV infection play in oxidative stress, lipid peroxidation, and disruption of cell function.Determine the source of proteins, known as cytokines, that act as antibody-mediated  messengers between liver cells, and their role in liver cell injury and regeneration in HCV-infected patients who use alcohol.Evaluate the effect of alcohol and HCV infection on fatty liver and determine how steatosis contributes to liver disease.Determine how alcohol use and HCV infection influence various types of liver cells .Characterize the effect of human liver cells  on overall human pathophysiology in response to alcohol and HCV.Identify genetic factors that affect the severity of alcohol- and HCV-induced liver disease.Develop animal models  of HCV infection and of alcoholic liver disease that reproduce disease processes found in humans.Excessive alcohol consumption among patients infected with chronic hepatitis C is likely to result in more severe liver injury, promoting cirrhosis and increasing the risk for development of liver cancer . Although the mechanisms by which chronic hepatitis C progresses to more severe liver disease in alcoholic patients have not been clearly established, they may include an alcohol-induced increase in viral replication; rapid mutation of HCV, leading to greater viral complexity; increased liver-cell death and inflammatory response; suppression of immune responses; accumulation of fat in the liver; and accumulation of excess iron in body tissues.In addition to greatly heightening HCV-infected patients’ risk of serious liver disease, heavy drinking during antiviral (interferon) treatment has been shown to impede patients’ responses to therapy. Abstaining from drinking before and during treatment improves patients’ response to antiviral therapy, although this improvement is not total. In light of these findings, alcoholic patients should be advised to abstain from further alcohol consumption and should be alcohol free for at least 6 months before beginning interferon therapy.Future research should further examine the effects of light and moderate drinking on features of the hepatitis C virus; alcohol’s effect on virus activity and response to treatment; patients’ immune responses to the virus; mechanisms of fibrosis in response to HCV infection and alcohol use; and animal models of HCV infection that may shed greater light on disease processes in humans.


The WHO recommends exclusive breastfeeding of infants for the first 6 mo of life (EBF-6). We reviewed the evidence behind concerns related to this recommendation. The risk of iron deficiency among EBF-6 infants can be significantly reduced if delayed cord clamping is performed in all newborns. At the moment there is no population-level evidence indicating that exclusive breastfeeding for 6 mo compared with <6 mo increases the risk of developing food allergies. Mild to moderate maternal undernutrition may reduce amounts of some nutrients in breast milk but does not directly diminish milk volume. Persistent reports of insufficient milk by women globally are likely to be the result of lack of access to timely lactation counseling and social support rather than primary biological reasons. All newborns should have their growth, hydration status, and development carefully monitored. In instances where formula supplementation is required, it should be done under the guidance of a qualified provider taking into account that early introduction of breast-milk supplements is a risk factor for early termination of exclusive breastfeeding and any breastfeeding. We found no evidence to support changes to the EBF-6 public health recommendation, although variability in inter-infant developmental readiness is recognized. We suggest that infant and young feeding guidelines make clear that complementary foods should be introduced at around 6 mo of age, taking infant developmental readiness into account. The literature reviewed was identified through a scan of review articles, recommendations from professional societies, scientific reports from the WHO, and the National Academies of Science, Engineering and Medicine; the authors’ files; and by eliciting feedback from experts based in academic institutions and at UNICEF, the WHO, and the Bill & Melinda Gates Foundation.In 2001, the WHO recommended exclusive breastfeeding (EBF) for the first 6 mo of life (EBF-6), replacing its previous recommendation of EBF for 4-6 mo ; howevern = 9) and high-income countries (n = 11). All but 2 of these studies were observational. The 2 randomized controlled trials (RCTs) were conducted in Honduras and included low-birth-weight (LBW) and adequate-birth-weight term (≥37 wk) infants who were receiving EBF for different durations. In both studies infants were provided with safe and nutritious complementary foods (1) there was no weight gain or linear-growth benefit for introduction of complementary foods at age 4 mo instead of age 6 mo (2) EBF-6 (compared with EBF-4) increased the risk of iron deficiency as indicated by low hematocrit, especially among LBW infants (1) no significant differences were found in growth among EBF-6 children compared with those with other EBF durations; 2) a lower incidence of gastrointestinal infection among EBF-6 infants was found when compared to infants receiving EBF for shorter durations; and 3) there was a potential risk for development of iron-deficiency anemia before age 6 mo, especially among exclusively breastfed infants born with suboptimal iron reserves and among LBW infants   . The EATRecommendations on the introduction of potentially allergenic foods in high-income countries remains controversial. The United Kingdom's Scientific Advisory Committee on Nutrition recently concluded  that wheA recent RCT from Ecuador found that introducing eggs between 6 and 9 mo and feeding 1 daily for 6 mo improved linear growth without increasing the risk of egg allergy . FurtherA previous evidence review concluded that changes to the EBF-6 public health recommendation were not needed because of general concerns about severe food allergy, but individual infants suspected to be at high risk should be assessed by a qualified provider to determine potential risk of developing severe allergy to certain foods and timing for their introduction . Recent Based on findings from the Canadian Healthy Infant Longitudinal Development cohort study, Miliku and Azad  concludeIn summary, providing small tastes of potentially allergenic foods under medical supervision to 4 to 6 mo old infants at high risk of developing food allergies  has been endorsed by several professional allergy societies in high-income countries for the purpose of preventing future food allergies , 67. HowIt is important to note that the aforementioned studies were carried out in populations of infants at risk of developing severe food allergy. There is presently no population-level evidence indicating that EBF for 6 mo compared with <6 mo increases the risk of developing food allergies. Hence, a change to the EBF-6 recommendation for the population at large to prevent food allergies is unwarranted.Self-reported insufficient milk (SRIM) is the most commonly mentioned reason provided by women the world over for introducing breast-milk substitutes into the infant's diet or for stopping breastfeeding altogether . Some haThe evidence suggests that delayed onset of lactation (DOL), i.e., when the copious production of milk does not begin within 72 h postpartum, increases the risk of SRIM and short breastfeeding durations, and can result from pre-lacteal feeds  that interfere with the infant's suckling process . ModifiaIn summary, SRIM leads to shortened breastfeeding durations, perhaps as a result of introduction of pre-lacteal feeds in response to DOL or perceptions of breastfeeding inadequacy as a result of infant crying, not feeling breasts full, or not seeing milk flowing from nipple , 89, 90.The WHO committee issuing the EBF-6 recommendation in 2001 acknowledged the dearth of evidence they had available to assess how EBF impacts maternal nutrition. It also recognized the lack of evidence on human milk meeting all infant nutrient requirements . In fact1) infant protein and energy needs can be met through EBF-6; 2) the adequacy of some nutrients (such as vitamin A and vitamin B-6) depend on maternal diet; 3) calcium quantity in breast milk is tightly regulated and does not depend on maternal intake; 4) human milk is low in iron and by 6 mo is also relatively low in zinc, and the concentrations of these nutrients in breast milk cannot be altered through maternal supplementation; 5) the potential for the EBF-6 infant to become iron-deficient should be considered, especially among LBW/premature infants. These conclusions, which echoed the Institute of Medicine (IOM) 1991 seminal report on human lactation , and energy concentration across populations, regardless of maternal nutritional status , 102. ThThis finding is consistent across studies even when different human milk sampling and analysis methods are used to determine macronutrient content; and also, when socioeconomic, nutritional status, and demographic characteristics—including infant age at which milk samples were obtained—vary within the populations assessed.In the field of human milk composition, vitamins and minerals are classified into 2 groups, depending on whether or not they are responsive to maternal nutritional status  Table 2, 103. ByWhen a breastfeeding mother ingests nutrient supplements, complex metabolic processes may allow for only a very small amount of these supplement-derived nutrients to enter the breast milk. Indeed, wide variability exists in how individual infants respond to similar amounts of maternal supplementation, and for some nutrients the amounts of maternal supplementation would need to be exceedingly high to meet infant requirements , 124. ThA 2013 review confirms the presence in breast milk of nutrients that are responsive (group 1) and nonresponsive (group 2) to maternal nutritional status in low- and high-income country settings . For groWith regard to group 2 nutrients, studies in a rural Mexican Otomi population confirmed that maternal folate status is unrelated to folate concentration in human milk, and that folate concentration in breast milk cannot be altered through maternal supplementation . EBF infAmong urban Bangladeshi women, the effects of maternal supplementation on human milk content were detected within 2–4 h for thiamin, riboflavin, vitamin A, and vitamin B-6, although the fraction transferred to breast milk ranged from 0.1% to 6.17% . ResponsConcentrations of vitamin D in human milk correlate with maternal vitamin D intake and sunlight exposure. The concentration of vitamin D in breast milk, even for healthy lactating women, is low. Breast milk does not provide infants with adequate vitamin D intake, even in populations typically known to be well nourished, and especially when infants are not exposed to sufficient sunlight . BecauseNutrient composition of human milk is a contributing factor to the nutritional status of the EBF infant. However, it is not the only contributor, as infants can self-regulate energy and nutrient intakes by adjusting the volume of milk they consume. The Honduras RCT mentioned previously found that all groups of infants exclusively breastfeeding for 6 mo compared with 4 mo  consumedThe finding that infant demand drives breast-milk production and subsequent consumption has been reported in multiple studies in high-income countries , 134. FoStuff and Nichols , demonstIn summary, despite evidence documenting that human milk responds to maternal nutritional status for some key nutrients for which the infants in low-income countries may be compromised, we have gaps in our knowledge about how several nutrients are metabolized and transported in human milk, and this has hindered the development of specific public health recommendations for nursing mothers . QuestioIncreasingly, infant-feeding guidelines, especially those from high-income countries, are acknowledging that there is a relatively wide variability on the exact age at which individual infants are ready to start complementary feeding . From a Evidence indicates that most infants will be developmentally ready to handle and benefit from the introduction of complementary foods at around age 6 mo , 147. HoThe WHO EBF-6 recommendation issued in 2001 , and basThe persistent reports of insufficient milk supply by mothers as a reason for supplementing breast milk with infant formula can be explained by the lack of adequate lactation management and social support rather than for primary biological reasons that cannot be properly addressed through sound lactation management. Studies have shown that lactation support during the first days and weeks after birth is central to successful establishment of lactation and to minimizing the risk of subsequent lactation difficulties , 78. IndThis Perspective also reaffirms that women with mild to moderate malnutrition, who comprise the majority of undernourished women in LMICs, can produce enough milk volume provided infant demand is not restricted because milk synthesis is dependent more on infant suckling than on maternal nutritional status itself. Breastfeeding is highly protective against infant morbidity and mortality in settings where infectious diseases and undernutrition are common, and therefore is strongly recommended even though the amounts of some micronutrients in mothers’ milk may be suboptimal . It is iMoving forward, improving maternal nutrition should be a top global public health priority, not only to improve the quality of the milk for infant consumption , but also to improve the nutrition and wellbeing of the mother herself.The child-development literature confirms that there is variability in the age at which infants achieve the necessary developmental milestones to be introduced to complementary foods, and that, on average, this happens at around 6 mo. Parents, other caregivers, and health providers should be taught how to identify the developmental cues that signal readiness for complementary feeding.All newborns should have their growth, hydration status, and development regularly monitored. In the exceptional circumstances where formula supplementation may be called for, it should be done with careful oversight from a qualified provider, keeping in mind that early breastfeeding problems and corresponding introduction of infant formula are major risk factors for the early termination of both exclusive breastfeeding and any breastfeeding , 156–160Further research is needed to continue developing standards for human milk production, consumption, and composition in diverse settings and at different stages of lactation , 99. It A limitation of our Perspective is that we did not address the breastfeeding needs and outcomes among women in extreme circumstances such as starvation, or experiencing chronic diseases. Because that scope falls beyond the public health recommendation for EBF-6 and requires a personalized clinical approach, it is important that future reviews focus on those topics.In conclusion, the 2001 WHO EBF-6 recommendation was issued as a public health recommendation, which acknowledged that tailoring to individual infants’ circumstances would be required , and tha


Genome instability is a hallmark of cancer cells and can be accelerated by defects in cellular responses to DNA damage. This feature of malignant cells opens new avenues for tumor targeted therapy. MRE11-RAD50-NBS1 complex plays a crucial role in sensing and repair of DNA damage. Through interacting with other important players of DNA damage response, MRE11-RAD50-NBS1 complex is engaged in various DNA damage repair pathways. Mutations in any member of this complex may lead to hypersensitivity to genotoxic agents and predisposition to malignancy. It is assumed that the defects in the complex may contribute to tumorigenesis and that treatments targeting the defect may be beneficial to cancer patients. Here, we summarized the recent research findings of the role of MRE11-RAD50-NBS1 complex in tumorigenesis, cancer treatment and discussed the potential approaches of targeting this complex to treat cancer. From endogenous processes that induce DNA damage, such as reactive oxygen species and replication fork collapse, to exogenous genotoxic agents that attack DNA and produce various DNA lesions, such as chemical agents, ultra violet and ionizing radiations, human genome stability is challenged constantly in daily life . These lThe MRE11-RAD50-NBS1 (MRN) complex has a crucial role in DDR. It is one of the first sensors and responders to DNA damage and orchestrates DDR response in double-strand break (DSB), replication fork (RF) collapse, dysfunction of telomeres and viral invasion , 13, DNAIn addition to these activities, MRN triggers cell cycle checkpoint response by interacting with ataxia-telangiectasia mutated (ATM) and ATM-and-Rad3-related (ATR) proteins , which aBased on DDR deficiency in tumorigenesis and tumor development and the intriguing potential function of MRN complex in DDR for cancer treatment, we sought, in this review, to focus on the structure and biofunctions of MRN complex and its roles in tumor development, treatment efficiency and the potential as a target for anti-cancer therapy.The MRN complex controls biological outcomes of DNA damage by acting as flexible scaffold, combined sensor, signaling and effector complex via its dynamic states. It impacts three critical functions in processing of DNA stress: DNA binding and processing, DNA tethering to bridge DNA over short and long distance, and activation of DDR response and checkpoint signaling pathways. Its structure architecture underlies these diverse roles .MRN structure can be separated into “head”, “coil”, “hook” and attached adapter regions.The head region consists of two RAD50 ABC-ATPase domains and two MRE11 nucleases bound to the base of the RAD50 coiled-coils  and two breast cancer-associated 1 C (BRCT) domains which form the phosphorylated protein binding core, a MRE11 binding motif and an ATM binding motif  is a concept describing the situation in which either one or two alterations in genes have little effect on cells or orgasms alone but a combination of these defects is potent enough to induce cell death . SL in BThe relationship between MRN complex and PARPi has also been explored in various studies. In BRCA wild-type (BRCAwt) ovarian cancer patients, 18% of the patients exhibit RAD50 deletion, and this deletion is associated with significantly better overall survival (OS) and progression-free survival (PFS). In ovarian cell lines, deletion of RAD50 copy number leads to better responses to PARP inhibitors. These results suggest that in BRCAwt patients, expression level of RAD50 might be employed as a candidate marker for survival and responses to PARP inhibitors . While lin vitro and in vivo experiments. Inhibitor treatment . It. Itet alThese conflicting reports on the potential relations between each component of the complex (or the MRN complex as a whole) and the prognosis of different cancer types suggest that there is still no consensus on the role of MRN complex in cancer prognosis. Because prognosis of cancer can be influenced by various factors such as the stage, the treatment received, and so on. A more detailed discussion of the role of MRN complex under specific conditions may better address these roles.To date, although there is no consensus on the role of MRN complex in tumorigenesis and prognosis, the majority of the results support its potential application as a target in cancer treatment.et al [in vivo. These results prove that the use of antisense oligonucleotides can be a potential cancer prophylaxis [et al reported that ectopic expression of FHA-domain mutated NBS1 sensitizes cancer cells to radiation therapy through suppression of HR [It was reported that targeting MRN complex can halt cancer cell growth and migration  and senset al  enforce phylaxis . Ohara eon of HR .et al showed that downregulation of MRN complex can increase the sensitivity of squamous cell carcinoma cells to platinum-based drugs [et al used recombinant adenovirus containing a mutant RAD50 gene to disrupt MRN function and found that this treatment increases radiosensitivity in vitro and decreases tumor growth and accelerates tumor regression in vivo [siRNA knockdown of RAD50 sensitizes NSCLC cells to radiation therapy in vitro . In breaed drugs . Chang e in vivo . Combina in vivo .et al found that genotoxic stress-induced miR-494 production downregulates MRN complex and DNA repair, resulting in senescence and pathologic angiogenesis disrupt [Over the past two decades, an increasing number of microRNAs (miRNAs) and small noncoding RNAs have been identified as regulators of tumorigenesis and sensitivity to radiation therapy or genotoxic chemotherapies via modulation of DDR . Espinos disrupt .Oncolytic virotherapy employs lytic viruses that replicate selectively in cancer cells. There is a great potential that these viruses can be used along with other anticancer therapeutics. In certain type of oncolytic virotherapy, the ability of various oncolytic adenoviruses to interfere with MRN complex and inhibit the DNA damage response has been proved effective. This has raised great interest in combining this therapy with other DNA damaging treatments - for example, radiotherapy .et al [et al [Stracker et al  first deet al . Blackfol [et al  found thA modified oncolytic adenovirus mutant that lacks an antiapoptotic gene (E1B19K) is found effective in sensitizing pancreatic cells to DNA damage-inducing drugs . Subsequet al showed that proteins trafficking of MRN components along microtubules can be blocked by microtubule-targeting agents [Poruchynsky g agents . Retainiet al reported that the ability of the loading of MRN complex onto DSB sites can be inhibited by phosphorylation of MRE11 at S67, which blocks its binding to DSB. Accordingly, mutation at S767 renders MRN complex functional, restores DNA damage-induced cell-cycle arrest and extends the utility of genotoxic treatment [Chen reatment .Among several inhibitors of MRN complex, mirin is the most studied. Mirin inhibits MRE11-associated exonuclease activity, prevents MRN-dependent ATM activation, and abolishes the G2/M checkpoint and homology-dependent repair in mammalian cells . Its potThe histone deacetylase (HDAC) inhibitor Panobinostat can downregulate MRE11 and other proteins associated with homologous recombination and radiosensitize tumor cells , 171.Pomegranate extract can inhibit cell proliferation and stimulate apoptosis in breast cancer cells. This anticancer effect may be mediated by its ability to downregulate the expression of molecules of MRN complex and other important genes involved in DSB repair .Heat shock protein 90 (Hsp90) is an evolutionary conserved molecular chaperone for numerous oncoproteins and is considered as an important facilitator of oncogenes. Its inhibitor compromises the ability of the MRN components to form nuclear foci and diminish the interaction between NBS1 and ATM, thus abrogating DSB repair in cancer cells . TargetiWith its important role in DDR, the function of MRN complex in cancer development and its potential as anticancer target has been widely explored in various types of cancer. It maintains genome stability and prevents malignant transformation in normal cells, but also functions in cancer cells. Many questions remain to be addressed with respect to its role in cancer. For example, there is little information about how MRN complex recognizes DNA ends, and a better delineation of the process should lead to a better understanding of its function. Also, the role of MRN complex in DSB and immune responses needs to be better explored. It is still controversial with respect to its dual role in tumorigenesis and prognosis. It appears that MRN complex is not critical for the development of cancer because most researches tend to consider the MRN complex as risk genes with moderate penetrance. Of note, most of the previous studies have been focused on investigating the relation between a single gene of the complex and cancer risk while often neglecting the state of the entire complex. Because each protein in the complex interacts with one another, the sole focus on individual component might yield information subjected to misinterpretation. To solve this issue, a standard for measuring and evaluate MRN complex as a whole is needed. Furthermore, combination of MRN disruption with PARPi appears to be a promising avenue for precision medicine. This might be realized through implement of oncolytic virotherapy or potent inhibitors. However, the exact synergistic efficacy of MRN complex deficiency and PARPi (or other treatments) require additional evidence at both the basic research and clinical level.


The rates of ribosome production by a nucleolus and of protein biosynthesis by ribosomes are tightly correlated with the rate of cell growth and proliferation. All these processes must be matched and appropriately regulated to provide optimal cell functioning. Deregulation of certain factors, including oncogenes, controlling these processes, especially ribosome biosynthesis, can lead to cell transformation. Cancer cells are characterized by intense ribosome biosynthesis which is advantageous for their growth and proliferation. On the other hand, this feature can be engaged as an anticancer strategy. Numerous nucleolar factors such as nucleolar and ribosomal proteins as well as different RNAs, in addition to their role in ribosome biosynthesis, have other functions, including those associated with cancer biology. Some of them can contribute to cell transformation and cancer development. Others, under stress evoked by different factors which often hamper function of nucleoli and thus induce nucleolar/ribosomal stress, can participate in combating cancer cells. In this sense, intentional application of therapeutic agents affecting ribosome biosynthesis can cause either release of these molecules from nucleoli or their de novo biosynthesis to mediate the activation of pathways leading to elimination of harmful cells. This review underlines the role of a nucleolus not only as a ribosome constituting apparatus but also as a hub of both positive and negative control of cancer development. The article is mainly based on original papers concerning mechanisms in which the nucleolus is implicated directly or indirectly in processes associated with neoplasia. Nucleoli are present in all eukaryotic cells with exception of those that have lost their nuclei during differentiation. Their main role, ribosome production, seems to be conservative in animals, plants, and yeasts. This process includes transcription of ribosomal DNA (rDNA), maturation of ribosomal RNA primary transcript (pre-rRNA), as well as assembly of ribosomal subunits and their transport to the cytoplasm , PI3K (phosphatidylinositol 3-kinase), Ras , and c-Myc  take part in the regulation of various stages of ribosome biosynthesis in normal cells, whereas their deregulation leads to intensified ribosome production which may contribute to tumorigenesis  is a multifunctional protein closely related to cell growth and proliferation. Under certain circumstances, NPM can trigger tumorigenic processes and be a potential oncogene even if NPM can activate PI3K/AKT pathway  is a phosphoprotein with a lot of cellular roles, including oncofunction. NCL because of its pro-tumorigenic activity is implicated in many mechanisms being direct or indirect chain link of various pathways characteristic of cancer development  is a protein detected in nucleoli of intensively proliferating cells, mainly stem cells and of several types of cancer cells, whereas its expression decreases in differentiating cells and disappears in fully differentiated cells. Hence, NS is thought to perform an important function in the control of cell proliferation , implicated in ribosome biogenesis and other cellular functions, is a novel negative regulator of p53, and thus, it acts as a potential oncogene. GRWD1 upon nucleolar stress migrates to nucleoplasm where it interacts with RPL11 and prevents blocking of Mdm2 activity. In consequence, p53 is degraded and the cell lacks anticancer protection in the form of p53-induced pathways , engaged in ribosomal subunit maturation and export, seems to be crucial for regulation of p53 activity in osteosarcoma cells during nucleolar stress. When nucleolar function and structure are disrupted by actinomycin D (Act D) or doxorubicin (Dox), p53 pathways are activated; thereby, cell cycle arrest and apoptosis appear. According to this mechanism, RRP12 overexpression disrupts p53 stability and promotes cell resistance to cytotoxic stress, while RRP12 silencing enhances p53 activity and cell death. Thus, targeting RRP12 function in combination with the nucleolus-disintegrating agents could increase the efficacy of anticancer therapy  domain of pKi-67 (NIKF) is a protein residing both in cytoplasm and in a nucleolus where it is involved in rRNA maturation  are implicated in the regulation of processes connected with carcinogenesis. Small nucleolar RNAs (snoRNAs) until recently were seen as housekeeping ncRNAs necessary mainly for pre-rRNA processing. Now, it should not be surprising that they are involved in neoplasia as ribosome biogenesis itself drives this process. Hence, participation of some snoRNAs in transformation and cancer development, during which deregulation of their expression occurs, is tightly related to enhanced ribosome production and more efficient cell proliferation and invasion. U3 and U8 snoRNAs are upregulated in many cancer types, including breast cancer, whilst under U3 or U8 depletion, the tumorigenic potential of lung and breast tumors decreases considerably and p53-induced apoptotic pathways are activated  regulates proliferation of hematopoietic cells negatively, thus it is accepted as a cancer suppressor, whereas its reduced expression or activity can lead to leukemogenesis, including chronic myeloid leukemia (CML) or AML. SHIP1 accumulates together with i.a. p53 in nucleolar vacuoles (nucleolar cavities) of both normal and leukemic hematopoietic cells. Nucleolar sequestration of SHIP1 is suggested to be the mechanism limiting its suppressive function, and thus, it may contribute to tumorigenesis  occurs mainly in a nucleolus, but it can also function in the nucleoplasm. ARF is a cancer suppressor, and hence, loss of its suppressor function appears in c.a. 40% of human cancers  activity results in lack of phosphorylation of Ltv1, a factor involved in the maturation of small ribosomal subunits . This causes a permanent bond between this factor and pre-40Ss and prevents their maturation, and thus, the number of functional ribosomes decreases which leads to inhibition of cell proliferation and growth. Since CK1δ/ε overexpression is observed in several types of malignancies , is involved in processes such as cellular senescence and apoptosis. In addition, it regulates PTEN activity and is responsible for nucleolar localization of some proteins, including NS  is a protein belonging to U3 proteins (t-UTPs) coordinating i.a. rDNA transcription through cooperation with UBF-1 and its acetyl-transferase hALP at rDNA promoter gene. The lack of UBF acetylation resulting from siRNA-mediated knockdown of 1A6/DRIM activity impairs initiation of RNA polymerase I-directed transcription and ribosome production. Then, ribosomal stress leads to activation of p53 pathway and to cell cycle arrest. On the other hand, 1A6/DRIM upregulation, promoting cell proliferation, occurs in certain cancer types  also known as the glioma tumor suppressor candidate region 2 (GLTSCR2) is a human nucleolar factor involved in ribosome biosynthesis, mainly in rDNA transcription and ribosomal subunits assembly. Disruption of PICT-1 functioning impairs ribosome production at various stages, thus leading to the activation of pathways directing cells towards concrete fates. PICT-1 is phosphorylated by ataxia–telangiectasia-mutated (ATM) kinase in a nucleolus which guides it to the proteasomal degradation in the nucleoplasm, among others in response to DNA damages. Decreased PICT-1 level elicits nucleolar stress followed by release of RPL11 from a nucleolus to the nucleoplasm, where RPL11 inhibits Mdm2 action and activates p53-mediated apoptotic pathway  inhibit Mdm2 activity and maintain the structural integrity of nucleoli . However, ribosomal or nucleolar perturbations can promote cancer in certain situations. Such a situation is observed in colorectal cancer cells that first are subjected to the ribosome-inactivating stress (RIS) and next to anticancer agents. RIS imposes chemoresistance, i.e., it restrains death of cancer cells and increases their chance for survival following anticancer drug administration which ultimately impairs the efficiency of chemotherapy  , it can also activate p53-independent pathways leading to modulations of cell cycle checkpoints via nucleolar ATM/ATR signaling  activation results in promotion of apoptosis as well as reduction of proliferation and migration of these cancer cells , which is present in ca. one-third of patients with AML, does not induce nucleolar stress. Furthermore, it prevents neither Act D-induced nucleolar stress nor activation of the p53-dependent and independent pathways leading cells to death by apoptosis or necrosis, respectively. Since NPM status is not so important in the case of leukemias, AML patients with NPMmut may be expected to have a better outcome of therapy, which is associated with cellular localization of NPMmut , as ubiquitous environmental contaminant also abundantly present in tobacco smoke, elicits dangerous diseases. Paradoxically, toxicity of Acr makes it a potential agent to be used for killing cancer cells regardless of p53 status. Acr preferably binds to nucleolar DNA causing oxidative damage of rDNA. This leads to nucleolar disintegration, thereby preventing rDNA transcription and ribosome biogenesis which induces RPL11-mediated apoptotic pathways as a response to nucleolar stress in human cancer cells with active and inactive p53 /K-RAS downstream pathways in gastric cancer cells. In addition to RAF/MEK/ERK pathway, also the axis with mTORC1 is responsive to MEK inhibitors which results in their lowered activity and thereby in reduced cell proliferation. The reduced phosphorylation of RPS6 is observed in these cases. This feature could be used prior to treatment to select those gastric cancer patients who are sensitive to MEK inhibition (Hirashita et al. A growing number of new data concerning nucleoli make this nuclear suborganelle less and less mysterious. Just over 2 decades ago, the nucleolus was solely perceived as a ribosome factory. Since then, it has been shown to be a plurifunctional structure involved in many crucial cellular processes, many of which also concern cancer cells. On one hand, ribosome biosynthesis itself and a number of nucleolar factors drive transformation and cancer development; on the other hand, vulnerability of cells to impairment of ribosome biogenesis may help to fight cancers. Moreover, changes of nucleolar morphology and of many nucleolar factors give valuable information in diagnosis of several cancer types.Participation of a rather small number of nucleolar and ribosomal proteins both in signaling pathways favoring carcinogenesis and in those that combat cancer cells has been confirmed so far. Attribution of new functions to proteins connected with nucleolus and ribosome biosynthesis whose roles are already known as well as functional decipherment of many new proteins that were identified to reside for longer or shorter time in nucleoli whose roles have not been specified yet, will undoubtedly take place in the near future.Moreover, development and introduction of new molecular methods increasing expression of nucleolus-associated molecules activating known pathways and discovering new pathways and nucleolar factors or factors interacting with nucleolar ones participating in destroying undesired cells as well as searching for new inhibitors targeting pathways leading to transformation and cancer development which can enhance the effect of the agents whose effect was disappointing are the challenges facing cancer researchers. Furthermore, search for and application of ways and factors enhancing responsiveness of cancer cells that acquired resistance to a given drug could make chemotherapy more effective.Moreover, most chemotherapeutic agents are usually toxic towards normal cells, causing side effects. Minimizing adverse effects considerably improves therapeutic efficacy and comfort of patients. That is why, it is very important to develop new approaches reducing undesired toxicity in non-malignant cells and to introduce them into the therapeutic course. Although the mechanisms of selective disruption of different stages of ribosome biosynthesis by different chemotherapeutics are well known, the exact mechanisms and factors contributing to selective elimination of cancer cells through drug-induced nucleolar stress which simultaneously do not harm healthy cells are not quite so well known yet. It was proved that intense ribosome biosynthesis, which is characteristic of many cancer types, is vulnerability of these cells that can be readily targeted. Indeed, cells with high rate of ribosome production are much more sensitive to perturbation of this process than those characterized by low rate of rRNA synthesis. Selective inhibitors of ribosome biosynthesis may cause cytotoxic effects leading to apoptosis of the cancer cells, while only cytostatic effects, i.e., transient cell cycle arrest of the healthy cells. As most cellular responses to inhibition of ribosome biosynthesis are mediated by p53, wild-type p53 and its high enough level during nucleolar stress in malignant cells is a prerequisite for the induction of apoptosis in them, whereas tumor cells with low rRNA synthesis rate should be additionally intervened with a drug that would rise p53 level enough to effectively address them toward death (Scala et al. Cyclotherapy seems to be an interesting cytoprotective strategy which could use induction of p53-mediated nucleolar stress response in the form of reversible cell cycle arrest triggered by specific perturbation of ribosome biosynthesis at certain stages in conjunction with cytotoxic treatment. This method might be used for selective killing of intensely dividing cancer cells that have lost p53 in p53-independent manner and for sparing proliferating non-malignant p53-proficient cells that become temporarily non-dividing ones. In addition, if any mutation associated with nucleolar functioning was a reason of cell transformation and cancer progression, then the product of mutated gene could be a specific target of the most promising modern chemotherapy, and personalized therapy/molecularly targeted therapy.Moreover, as malignant cells are characterized by deregulation of signal transduction and metabolic pathways, including those associated with cellular nutrition, the specific dietary regimen seems to be a promising strategy to promote differential effects in non-malignant and cancer cells. In this case, therapeutic effects are based mainly on the deficit of cellular energy which is utilized mainly for processes associated with intense proliferation of disregulated cancer cells. In addition to the fact that the cancer cells weakened by this deficit are notably sensitive to chemotherapeutic drugs, including ribosome biosynthesis-perturbing ones, oncogenes prevent the activation of stress resistance in them. Consequently, cancer cells are selectively killed, mainly by autophagy. On the contrary, normal starved cells halt cell cycle through insulin-like growth factor-1 and shift energy deficiency towards survival (Buono and Longo Summing up, disregulated signaling, resulting from altered genetic programs, connecting energetic metabolism, nutrient availability, cell growth, and proliferation, as well as ribosome and protein biosynthesis determines high sensitivity of cancer cells to appropriate chemotherapeutics in comparison to normal cells. Hence, detailed recognition of differences, including pathways and their players under various stress conditions, between cancer and normal cells would allow for more precise hit in targeted cells which would reduce or even eliminate side effects.


Asthma and influenza are two pathologic conditions of the respiratory tract that affect millions worldwide. Influenza virus of the 2009 pandemic was highly transmissible and caused severe respiratory disease in young and middle-aged individuals. Asthma was discovered to be an underlying co-morbidity that led to hospitalizations during this influenza pandemic albeit with less severe outcomes. However, animal studies that investigated the relationship between allergic inflammation and pandemic (p)H1N1 infection, showed that while characteristics of allergic airways disease were exacerbated by this virus, governing immune responses that cause exacerbations may actually protect the host from severe outcomes associated with influenza. To better understand the relationship between asthma and severe influenza during the last pandemic, we conducted a systematic literature review of reports on hospitalized patients with asthma as a co-morbid condition during the pH1N1 season. Herein, we report that numerous other underlying conditions, such as cardiovascular, neurologic, and metabolic diseases may have been underplayed as major drivers of severe influenza during the 2009 pandemic. This review synopses, (1) asthma and influenza independently, (2) epidemiologic data surrounding asthma during the 2009 influenza pandemic, and (3) recent advances in our understanding of allergic host–pathogen interactions in the context of allergic airways disease and influenza in mouse models. Our goal is to showcase possible immunological benefits of allergic airways inflammation as countermeasures for influenza virus infections as a learning tool to discover novel pathways that can enhance our ability to hinder influenza virus replication and host pathology induced thereof. Of the organ systems in the body that are exposed to the external environment, the pulmonary system is the most vulnerable due to its large surface area that accommodates a total of 10,000 L of air  daily. The upper and lower segments of the respiratory tract are bound by common structural and immunological components, allowing some infectious agents and secreted proteins in the upper respiratory tract to be transmitted to the lower respiratory tract. Therefore, the respiratory system must be considered as a whole when investigating disease pathogenesis and treatments, which is the basis of the “one-airway” concept.While physical barriers and innate immune defenses serve to protect the lungs from infections and damage, susceptible individuals may develop responses to (often) innocuous agents over a period of time leading to the development of asthma, a major chronic disease of the airways , 2. ReceRespiratory viruses, such as influenza A virus (IAV), respiratory syncytial virus (RSV), and rhinovirus (RV) are constantly circulating and can infect individuals of all ages, although the pediatric population is the most vulnerable . Simply Symptoms of asthma were described in the Chinese literature as early as the twenty-sixth century BC , while tIn spite of improved understanding of disease pathogenesis, the incidence of asthma in the western world has increased over the past 40 years, and it is now the most common chronic disease in the world  affectinAlthough the differences and similarities in disease etiology are unclear, various types of asthma, such as allergic asthma, exercise-induced asthma, cough variant asthma, occupational asthma, nocturnal asthma, and brittle asthma have been identified. Further classifications can be made based on the immune profile associated with the exacerbation , 21 addiAllergic responses consist of an early phase which occurs immediately after allergen exposure, and a late phase which starts 6–9 h following allergen provocation. The early phase reaction is initiated through localization and signaling of high affinity Fcε receptors on mast cells (and others) bound to antigen-loaded immunoglobulin E (IgE). IgE-mediated degranulation of these cells causes the release of histamine, prostaglandins, leukotrienes, and reactive oxygen species, all of which can result in smooth muscle cell contraction, mucus hypersecretion, and vasodilation. Vasodilation and microvascular leakage cause plasma protein exudation into the airways leading to edema. Furthermore, plasma proteins bypass epithelial tight junctions and accumulate in the airway lumen interfering with mucociliary clearance . Plasma The common symptomatologies of asthma  can be generic and shared by other respiratory conditions, such as eosinophilic granulomatosis with polyangiitis , allergiAsthma endotypes explain the various cellular cascades/pathways that manifest during different asthma phenotypes. The consensus between each endotype, however, is that the initiating trigger occurs at the bronchial epithelia , 46. TheH2 cytokines (H2 cells and type 2 innate lymphoid cells (ILC2s) that can produce amphiregulin (AREG)  fluid are higher in asthmatics compared to healthy controls . BAL fluytokines , includiytokines . Eosinopytokines , that coytokines , 55. IL-n (AREG)  a possibn (AREG)   , not alln (AREG) , highlign (AREG) , 61.Orthomyxoviridae family. These viruses are morphologically spherical to ovoid and can range between 80 and 120 nm in diameter  and respiratory  symptoms. The minor overlap of symptomologies between asthma and influenza are likely due to architectural reasons as immune responses vastly differ Figure . Immune Influenza viruses infect the airway epithelium and hijack the eukaryotic cellular machinery for rapid replication triggering both innate and adaptive immune responses , 70–72. Although innate immune cells are important in antiviral immunity , their oThe first case of the 2009 “Swine Flu” (influenza) pandemic was identified in Mexico in mid-February, following which the CDC reported swine origin H1N1 influenza in two samples collected from patients in California . This viUnlike seasonal influenza strains to which infants and the elderly have the greatest susceptibility, pH1N1 virus caused more severe disease in school-aged children, adolescents, and adults ranging between 5 and 24 years of age . AlthougNearly half of the hospitalized patients with Swine Flu had no reported co-morbidity , while vUnlike other influenza viruses that negatively impact “immunosuppressed” populations at either ends of the age spectrum, pH1N1 IAV strain caused hospitalizations in individuals between 18 and 50 years of age , 107. WhAsthma was an undisputed risk factor associated with hospitalization Figure  affectinLung diseases are often complex and multifactorial, and, can sometimes overlap. COPD was identified as a risk factor associated with worse outcomes . Asthma The age of onset and endotype often determines the chronicity of asthma and maintenance medication use. Patients that were not on long-term therapeutics to control asthma symptoms had a higher incidence of pH1N1 infection , 135. WhAsthmatics are generally considered inept at countering virus infections effectively due to immune bias. Information largely focusing on RSV and RV have shown that asthmatics have reduced type I IFN responses during respiratory infection . WhetherDisease severity during the Swine Flu pandemic was further marked by ICU admittance and death . IntriguVaccination and antivirals are available protectants prior to and during IAV infections. Annual vaccination against influenza infection is recommended by the WHO for all individuals but especially for pregnant women, children, and the elderly, and those with underlying health conditions. In spite of these recommendations, less than ~50% of the US population seeks the annual influenza vaccine . While vThe use of clinical data factors as both a strength and weakness in exploring outcomes of infection. Variability in available and reported data can contribute to differences in conclusions as evident in the literature that focused on asthma in hospitalized patients during the 2009 influenza pandemic. Since the combined percentages of diseases in some cohorts were over 100% Figure , it shouH2 cytokines  in the serum compared to those that did not  localized to the lungs to initiate acute features of asthma largely relying on granulocytic inflammation as a hallmark. The above referenced mouse models of asthma and influenza also predominantly focused on IAV infections in mice with “acute asthma” primarily because they were built to reproduce the clinical findings that asthmatics with exacerbations were protected from severe influenza disease. Very few mouse models are able to produce airway wall remodeling as a chronic feature of asthma . We haveORMDL3 has been linked to increase susceptibility to RV-induced wheezing and subsequent asthma diagnosis (H1 responses against respiratory viruses stems largely from investigations surrounding RV (H1, TH2, and TH9 responses (The strong gene:environment association that occurs in asthma also contributes to disease pathogenesis and response to viruses. For example, a single nucleotide polymorphism in iagnosis . Howeveriagnosis , suggestnding RV . A mixedesponses . Immune Asthma and influenza are common conditions that affect millions worldwide. Although pathogens like RSV and RV are known to initiate and exacerbate asthma, the relationship between asthma and influenza was ambiguous. The recognition that asthma was a risk factor associated with hospitalization during the 2009 influenza pandemic put these two diseases in the spotlight as a duo for poor outcomes. The notion that hypersensitivity-based immune responses may be protective to the host during pathogen encounters was first suggested by Arthur Varner , and conRV and AS wrote the manuscript. RV and AS analyzed literature and produced Figure The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.