Unexpected and increasingly frequent extreme precipitation events result in soil flooding or waterlogging. Legumes have the capacity to establish a symbiotic relationship with endosymbiotic atmospheric dinitrogen-fixing rhizobia, thus contributing to natural nitrogen soil enrichment and reducing the need for chemical fertilization. The impact of waterlogging on nitrogen fixation and legume productivity needs to be considered for crop improvement. This review focuses on the legumes-rhizobia symbiotic models. We aim to summarize the mechanisms underlying symbiosis establishment, nodule development and functioning under waterlogging. The mechanisms of oxygen sensing of the host plant and symbiotic partner are considered in view of recent scientific advances. Global population is expected to reach around 9.6 billion in 2050 , leading3) production in the last century, such as water and soil pollution (2)-fixing rhizobia, thus contributing to natural N soil enrichment and reduced need for chemical fertilization. These crops are also a key protein resource for human and animal foods.In agriculture, the conversion to alternative, more ecologically sustainable sources is moving toward productive systems that reduce the input of fertilizers. Nitrogen (N) is one of the most important nutrients for crops and today a reduction in crop dependence on chemical N fertilization is essential. This is due to the cascade of environmental changes resulted from the huge increase of ammonia  diffusion path under waterlogging via physiological adaptation. An increased aerenchyma network in the root and nodule cortex, the presence of a barrier to radial O2 loss in the outer root tissues and an increased permeability of the nodule O2 diffusion barrier (ODB) can facilitate tolerance  are characterized by a persistent meristem and a continuous growth, while determinate nodules  are characterized by a not persistent meristem and a limited growth potential.Several studies have considered the waterlogging effect on nodulation capacity. Hypoxia-sensitive legumes, such as pea , alfalfa hypoxia . Two stu hypoxia ,b reportMelilotus siculus, nodules formed during waterlogging stress have been observed above all on adventitious roots . Hypoxia generates NO in plants, likely with the presence of a cyclic respiration that improves the plant’s capacity to tolerate hypoxic stress by maintaining the cell energy status  and Cys residue in the second position of the protein. ERF-VII proteins are degraded via the N-end rule-dependent proteasome pathway triggered by Plant Cysteine Oxidases (PCOs) in an O2-dependent manner (The Ethylene Responsive Factor group VII family (ERF-VII) guides the response to Osurvival . In Arabt manner .2, NO destabilizes ERF-VIIs, and a reduction in the availability of either gasses is sufficient to stabilize them  harbors four genes that belong to the ERF-VIIs group  domain and a C-terminal histidine kinase domain  modify the perception of the partner during the symbiotic establishment, (ii) influence the nodule development, and (iii) affect the functioning of the nitrogenase enzyme in the bacteroid. These aspects may be further influenced by the high level of NO encountered in the nodule organ, which is involved, together with O2, in ERF-VIIs degradation. At the same time, the PNR cycle may offer an alternative way to produce energy under O2 shortage. A detailed analysis of these steps would help in finding interesting solutions for marginal land cultivation with waterlogging tolerant legumes capable of fixing N2 where limited O2 is available.The study of symbiotic models in response to waterlogging can help in deciphering the mechanism that may be crucial for the isolation of tolerant legume crop species and varieties in the field. The steps in signal exchange for the mutual recognition, nodule organogenesis and efficient NCP and AB conceived the idea of the review. All the authors were involved in the manuscript writing.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.


The conflict environment in Libya is characterized by continued pervasive insecurity amidst the widespread availability of small arms and light weapons (SALW). After the First Civil War, armed brigades took the law into their own hands and the resulting violence terminated a short-lived post-conflict period that has relapsed into a Second Civil War. The Libyan government has struggled to assert authority over armed groups and these brigades, refusing to disarm have contributed directly the initiation of a second conflict; some are motivated by self-defense, status, criminality, vindication or political aims.Once, a bastion of public health in the Middle East and North Africa (MENA), the country now faces a substantial and unprecedented challenge: to rebuild a devastated health system amidst the burden of armed violence and the proliferation of small and light weapons (SALW) especially firearms of various kinds. The health system in Libya is compromised; healthcare professionals have little time to record or document such cases given the immediate clinical needs of the patient. This corresponding decreased capacity to deal with an increasing demand on services caused by SALW-related morbidity compounds the challenge of data collection and indicates that external support and advocacy are required.A public health strategy towards effective SALW armed violence reduction and injury prevention requires the interdisciplinary advocacy of practitioners across the fields of justice, security, development, health and education. Through surveillance of firearms and injuries in the post-conflict environment we can better evaluate and respond to the burden of armed violence in Libya. In order to reduce armed a reconceptualisation of arms reduction campaigns must occur. Notable emerging evidence recommends the inclusion of community-based interventions and development programs which address local motivations for firearms ownership alongside improved international coordination. This renewed approach holds importance for recovery, development and securing the transition to peace.The high prevalence of firearm ownership, weak institutions, nascent security forces, porous borders, inadequate weapons stockpiles, combined with high military spending, compounds public weaponisation as a health crisis for the entire MENA region. The conflict environment in Libya is characterized by a widespread availability of small arms and light weapons (SALW). Once a bastion of public health in the Middle East and North Africa, the country now faces a substantial challenge: to rebuild a devastated health system amidst the scourge of SALW proliferation and relapsing civil war . The IntLibya is a middle-income country, with a pre-war population of approximately 6.4 million people , of whicNo single policy can address health in a complex and relapsing conflict environment such as Libya . ViolencJamahiriya [Since 2011, the health system of Libya has been heavily affected by armed conflict. The Libyan uprising and the First Civil War was an eight-month internal armed conflict lasting from 17th February to 23rd October, 2011. It officially ended with the killing of Muammar al-Gaddafi, the former leader of Libyan Arab mahiriya . The civmahiriya  has term‘zanga zanga’ speech which incited ‘street by street’ cleansing [The armed insurrection was subsequently supported by a NATO ‘Right to Protect’ (R2P) operation under the auspices of Resolution 1973. This international military intervention commenced in order to protect civilians for humanitarian reasons following Gaddafi’s televised leansing . The aimleansing .By the end of the first period of the conflict there was in excess of 125,000 SALW in the hands of militias ( p.i). AfThe impacts of violent armed conflict in Libya are long-term; victims are usually young males but also include other vulnerable groups, particularly those of Tawerghan or sub-Saharan African background . The perSALW proliferation is a dangerous consequence of armed conflict. It is further facilitated through illicit trafficking in combination with inadequate disarmament, demobilization and reintegration (DDR) programs. While the proliferation of arms is not considered the cause of violence, it does increase the severity of violence as a force multiplier ( p.113). The indirect effects of armed violence include the disruption of livelihoods through population displacement leading to pervasive insecurity , 62. MorA range of pragmatic local interventions with the aim of mitigating the destructive consequences of violence can then be achieved . In LibySALW control is increasingly recognised as a public health good, especially in the post-conflict environment  , 48. RehBefore the onset of the 2011 civil war, Libya’s homicide rates were at 2.9 per 100,000 people. Accurate homicide figures since the onset of the war are not known. Although the International Institute for Strategic Studies (IISS) reports 30,000 combat-related deaths in 2011 and 828 deaths in 2012 , which wRecorded data quantifying the extent of availability of SALW in Libya is uncoordinated and varying in quality. Initiatives to convert these recordings into a centralised dataset would allow for increased oversight . Prior tThe price of SALW is correlated with increased availability, and evidence suggests that cheap and plentiful guns increase the risk of violence ( Ch. 7). In Libya there are approximately 147 separate rival tribes and hundreds of different armed groups. Consequently, this creates a very complex security environment. The potential is clear; Duquet  recognisLibya’s relatively homogenous population is at risk of fragmentation along ethnic, tribal and federal fault lines. Escalating tensions and mistrust between black Africans and Berbers in Kufra for example have resulted from their respective stereotype as either pro- or anti-Gaddafi . Newly cThe high rates of ex-combatant unemployment combine with the prestige status afforded to SALW owners. This problem relates to the cultural and symbolic status the weapon has within society . Under GCorresponding poverty through lack of employment and failure of reintegration may also lead ex-combatants to armed violence as a means of livelihood . TrafficThe relapsing conflict environment in Libya is characterized by the widespread availability of SALW. The new Government of National Accord now faces the substantial challenge of rebuilding a health system amidst ongoing political tensions and the burden of significant SALW-related injuries and disability. Recognition of a coordinated interdisciplinary policy strategy is therefore necessary in addressing and managing this preventable issue . Table 1Geneva declaration on Armed Violence and Development was aimed at supporting state actors and civil society organisations to reduce the burden of armed violence [The 2006 violence . This buviolence , 49.Prior to 2013, the arms trade was regulated by the Programme of Action, and regional controls. The 2013 Arms Trade Treaty (ATT) is the first international legally-binding instrument to control transfer of conventional arms. The treaty is intended to limit conflict diversion, corruption and improve responsibility for arms deals. An ATT which controls the availability and transfer of small arms is important, but necessitates international enforcement procedures to ensure the legitimacy of the ATT.Successful comparisons for injury prevention must be grounded in previous public health experience. Pinto et al.  argue foFaina which was hijacked by Somali pirates [Multilateral trade commitments for conventional arms that pledge minimum standards for responsible trade are a promising avenue for the reduction in the supply of SALW to non-state actors. The ATT contains a categorical prohibition on the transfer of SALW and ammunition to a state which may be capable of commission of genocide, crimes against humanity or war crimes . The tre pirates .Collier  states tA highly fragile security environment has emerged in the Sahel . The mobCollier’s economic analysis through statistical modeling indicates that military spending is correlated with increased risk of re-entry into conflict . Cost-efMilitary spending in fragile-states is excessive by any standards. Collier’s , 45 statThere is potential for brigade commanders to exercise their authority for the disarmament of SALW and reintegration of their combatants – provided of course that some compromises be made . PoliticCommunity organizational hierarchies pose a vital opportunity to motivate former commanders and elders to implement measures to reduce SALW violence. Such initiatives have already been proven effective in Colombia; an effective alternate-day public ban on carrying firearms was enforced in Bogota and was associated with a reduction in homicide rates . CorrespWeapons reduction programs combined with DDR show successes when they are adequately prioritized . The IntSALW supply reduction through DDR campaigns forms an integral component of conflict management strategies . Demand-Voluntary cash incentives such as those used in buy-back programs in post-conflict Sierra Leone and Liberia should be approached with caution. Despite the successful destruction of thousands of SALW , some arExpanded efforts with community-based finance initiatives have shown major successes in Central America and the Caribbean  are vital for the initiation and maintenance of SALW reduction in Libya. This is challenging given that Libya’s institutions have undergone appreciable neglect over the 42-years of Gaddafi rule and 7 years of conflict and insurgency.The establishment of integrated legislation focusing on armed violence reduction is required in the medium to long-term. Laws regarding registration of firearm ownership, restrictions such as age limits, waiting periods, and background checks have all proved effective to varying degrees ( Ch.8). TCheap, durable, concealable weapons are flowing through Libya’s porous southern desert borders to where they are in highest demand. There were pre-existing illicit trafficking networks spanning from West Africa and spreading north towards the Mediterranean via the Tuaregs of the Sahel. Trafficking to and from the Maghreb; Algeria, Tunisia and Libya. The Libyan government has assured the UN that borders with Algeria, Chad, Niger, Sudan and Tunisia are now closed, and declared a restricted military zone in the southern region . ReintegThere is a notable difficulty in retrieving accurate data on arms transfers; especially those on the grey and illicit black market. This highlights the importance of collecting data on SALW flows, stockpiles and price. In Libya, years of UN and EU embargo deterred legal arms supply and may have initiated illicit trafficking and diversion from neighbouring countries . Small AArmed violence reduction and injury prevention requires the advocacy of interdisciplinary practitioners across the fields of criminal justice, security, development, health, policy, anthropology and education. Through surveillance of SALW and public health injury reporting we can evaluate the burden of armed violence in Libya. Kruk et al.  argue thUnfortunately, Libya demonstrates the severe health and human rights consequences that occur due to failure of these processes. We know that DDR and weapons reduction campaigns alone will not effectively reduce the demand for SALW. The post-conflict environment therefore requires a diverse package of DDR, second generation weapons reduction, SSR, judiciary and legislative interventions. At this time of great instability for the Libyan Government an SALW weapons reduction strategy holds importance for ‘recovery and development’ and securing the transition to peace . In this


Our current understanding of the integral membrane protein structure and function has changed dramatically in the last two decades, thanks to novel experimental, and methodological approaches that take advantage of the latest technologies. From the earliest high-resolution crystallographic studies on bacteriorhodopsin .Membrane proteins represent a challenging family of macromolecules, particularly related to the methodology aimed at characterizing their three-dimensional structure. This is mostly due to their amphipathic nature as well as requirements of ligand bindings to stabilize or control their function. In this perspective article, Sun and Zheng focus their review on the unique properties of a dual function nitrate transporter NRT1.1, a member of the nitrate transporters superfamily in plants, which may switch between low- and high-affinity states to cope with the large nitrate fluctuation in soil. By means of structural studies on NRT1.1 in Arabidopsis, they show that single residue phosphorylation leads to changes in protein oligomerization. Notably, such secondary changes in protein oligomerization are sufficient to increase structural flexibility of NRT1.1 and to modify nitrate affinity. The authors propose a novel paradigm in which protein oligomerization and posttranslational modification can synergistically convey to modulate the functional capacity of dual-affinity transporters.+/Ca2+ exchangers, which extrude Ca2+ from the cell to maintain cellular homeostasis. Within eukaryotic cells, NCX proteins exist as a complex set of orthologs, isoforms, and splice variants expressed in a tissue-specific manner. In this research topic, Giladi et al. review the structural basis for the diverse regulatory responses to Ca2+ binding in different orthologs and splice variants in relation to the dynamic of the two regulatory Ca2+-binding domains, CBD1 and CBD2.Recent structural and biophysical studies have shed light on the structural basis of ion transport and the allosteric regulation of sodium-calcium exchanger (NCX) proteins. The NCX proteins include a family of NaZhang et al. review the recent structural findings of proton-translocating nicotinamide nucleotide transhydrogenase (TH). Transhydrogenase is an enzyme complex in animal mitochondria and bacteria that utilizes the electrochemical proton gradient across membranes to drive the production of NADPH. The enzyme plays an important role in maintaining the redox balance of cells, and it has been shown to have implications in aging and human diseases. Structural insights into the mechanism of dynamics of TH require structural determinations of the protein complex in many conformational states. Here, Zhang et al. compile the information from recent technological breakthroughs in X-ray crystallography and cryo-EM to outline a comprehensive and detailed structural understanding of this very complex enzyme.Clausen et al. review the various roles and expression patterns of the Na-K ATPase subunit  isoforms. The Na-K ATPase was first described 60 years ago by Skou . The article by Zeth and Zachariae reviews the most important advances on the structure and function of VDAC superfamily members, and the review summarizes how they enhanced our understanding of the channel.The major protein in the outer membrane of mitochondria is the voltage-dependent anion channel (VDAC), which mediates signal transmission across the outer membrane but also the exchange of metabolites, most importantly ADP and ATP. Over the past 10 years, complementary structural and functional information on proteins of the VDAC superfamily have been collected from Lang et al. suggest that this feature is linked to the regulation of ATP import into the ER and the initiation of the intrinsic pathway to apoptosis. Recently, cryoelectron tomography of translocons in native ER membrane vesicles has given unprecedented insights into the architecture and dynamics of the native translocon harboring the Sec61 channel. In this review by Lang et al., this structural information is discussed in light of different Sec61 channel activities including ribosome receptor function, membrane insertion, and translocation of newly synthesized polypeptides as well as the putative physiological roles of the Sec61 channel as a passive ER calcium leak channel.The mammalian Sec61 complex existing in the membrane of the endoplasmic reticulum (ER) forms a dynamic gated channel, which provides an aqueous path for nascent polypeptides in the cytosol into the ER lumen and is regulated by various allosteric effectors. Further, when the pore forming subunit of the complex (gated pathway) is open, it also provides a pathway for the efflux of calcium ions from the ER into the cytosol. A total of 27 renowned researchers from seven countries  have contributed to this research topic. We hope this compilation provides a stimulating knowledge base for upcoming research in this very active and promising investigation field.MD and GN have edited the research topic and have written and drafted the manuscript.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.


This work focused on a detailed assessment of lung tissue affected by metastasis of breast cancer. We used large-area chemical scanning implemented in Fourier transform infrared (FTIR) spectroscopic imaging supported with classical histological and morphological characterization. For the first time, we differentiated and defined biochemical changes due to metastasis observed in the lung parenchyma, atelectasis, fibrous, and muscle cells, as well as bronchi ciliate cells, in a qualitative and semi-quantitative manner based on spectral features. The results suggested that systematic extracellular matrix remodeling with the progress of the metastasis process evoked a decrease in the fraction of the total protein in atelectasis, fibrous, and muscle cells, as well as an increase of fibrillar proteins in the parenchyma. We also detected alterations in the secondary conformations of proteins in parenchyma and atelectasis and changes in the level of hydroxyproline residues and carbohydrate moieties in the parenchyma. The results indicate the usability of FTIR spectroscopy as a tool for the detection of extracellular matrix remodeling, thereby enabling the prediction of pre-metastatic niche formation. Cancer malignant behavior can be terminal. Tumors can spread into organs and invade nearby and further tissues. The leading cause of death in advanced stages of cancer is metastasis formation and its consequences . SeveralRecent studies have also introduced the concept of the pre-metastatic niche. This is the formation of a specialized microenvironment through extracellular matrix remodeling, immunosuppression, inflammation, and vascular hyperpermeability, created by the primary tumors in secondary organs and tissue sites for subsequent metastases ,4. ThereCancer-related processes transform several tissue structures ,6. Abnor−1) and DNA IR absorptions (1090–1080 cm−1) accompanied by an intensity decrease in the protein range (1800–1500 cm−1). In turn, studies of lung cancer via FTIR spectroscopy were conducted to establish the differences between cancerous and healthy lung tissue samples  and selected FTIR biomarkers was performed via the Spearman’s rank correlation coefficient (R) and probability (P) in SPSS Statistics 24  software.Mean second derivative spectra were used for the calculation of the integral intensity of various bands using the OPUS 7.0 program . For this purpose, a linear baseline was drawn through the peak edges, and the spectrum below this line was integrated over the wavenumber range of the band. Box plots were constructed for an analysis of variance performed using the statistical model (ANOVA) in the OriginPro 9.1 software. Tukey’s test was employed to compute significance values This study comprehensively described changes in proteins of the extracellular matrix in the lungs as being the primary site of metastasis in the mice model of breast cancer. Using large-area scanning implemented in FTIR spectroscopic imaging indicated molecular changes across whole cross-sections of the lungs giving insight into the separated tissue structures. We found that using FTIR spectroscopy; we obtained the biochemical information that allowed us to differentiate not only the type but also the degree of protein degradation. The spectral changes that appeared in lung parenchyma and atelectasis indicated a significant variation in secondary conformations of proteins and their composition. The former appeared similarly in both main constituents of the lung but the deposition of fibrillar proteins was specific for each of them. These alternations occurred before the invasion of breast cancer cells to the lungs suggesting that the amide I–III regions in the IR spectrum were sensitive to the signaling of the primary tumor. Consequently, this highlighted inflammation of the lung due to the transplantation of breast cancer cells recognized by H&E staining in the early phase and/or the formation of the ECM environment suitable for settling metastatic cancer cells.


Patients with suspected peri-operative anaphylaxis (POP) require thorough investigation to identify underlying trigger(s) and enable safe anesthesia for subsequent surgery. The changing epidemiology of POP has been striking. Previous estimates of the incidence of POP have ranged between 1:6,000 and1:20,000 anesthetics, but more recent data from France and the United Kingdom suggest an estimated incidence of 1:10,000. Other important changes include a change in the hierarchy of well-recognized triggers, with antibiotics (beta-lactams) supplanting neuromuscular blockers (NMB) as the leading cause of POP. The emergence of chlorhexidine, patent blue dye, and teicoplanin as important triggers have also been noteworthy findings. The mainstay of investigation revolves around critical analysis of the time-line of events leading up to anaphylaxis coupled with judicious skin testing. Skin tests have limitations with respect to unknown predictive values for most drugs/agents and therefore, knowledge of background positivity in healthy controls, test characteristics of individual drugs and the use of non-irritant concentrations is essential to avoid both false-positive and false-negative results. Specific IgE assays for individual drugs are available only for a limited number of agents and are not a substitute for skin testing. Acute serum total tryptase has a high specificity and positive predictive value in IgE-mediated POP anaphylaxis but is limited by its moderate sensitivity and negative predictive value. Planning for safe anesthesia in this group of patients is particularly challenging and consequently anesthetists need to be alert to the possibility of repeat episodes of anaphylaxis. Because of the limitations of current investigations for POP, collecting systematic data on the outcome of repeat anesthesia is valuable in validating current investigatory approaches. This paper reviews the changing epidemiology of POP with reference to the main triggers, and the investigation and outcome of subsequent anesthesia. Peri-operative anaphylaxis (POP) is a serious and unpredictable iatrogenic adverse effect associated with substantial morbidity. Fatalities associated with POP are rare but occur in a significant minority of patients. In a recent audit of POP in the United Kingdom involving administration of 3 million anesthetics over a 12 months period, 10 deaths, and 40 cardiac arrests were documented in 266 patients developing anaphylaxis of grade 3–5 severity  and non-depolarizing NMBs (benzylisoquinolines and aminosteroids) are capable of triggering POP via an IgE-mediated or non-IgE mediated pathways. Evidence for IgE-mediation is based on the demonstration of a positive skin tests and/or drug-specific IgE in serum. The ability of NMBs to trigger mast cell degranulation via the newly described MRGPRX2 receptor  raises tWhile the frequency of anaphylaxis with individual NMBs has not been systematically quantified, analysis of recent data from the French Pharmacovigilance Database ranked suxamethonium and rocuronium as the agents most frequently implicated in causing NMB anaphylaxis . SimilarThe place of beta-lactam antibiotics in the form of amoxicillin or co-amoxiclav as the leading antibiotic trigger for POP has recently been supplanted in the UK by teicoplanin . WhetherWhile there is increasing awareness of teicoplanin allergy amongst anesthetists, confirmation of allergy is challenging because of the limited sensitivity and lack of standardization of skin tests. In a recent series, 5 of 14 patients with either definite or probable teicoplanin-induced peri-operative anaphylaxis were negative on skin tests . Based oTwo other important findings have emerged from the UK national audit of POP . The useAlthough chlorhexidine is now well-recognized as a cause of POP occurring in 9.3 and 9.6% of cases in the UK  and DenmPatent blue dye, used for sentinel node biopsy during cancer surgery was identified in 5% of cases in the UK survey of POP . Blue dyA range of other drugs have been identified as triggers for POP including, Ondansetron, propofol, aprotinin, protamine, and ibuprofen in a small number of cases. Previous concerns about a possible increase in the risk of propofol allergy in patients with a history of egg allergy have proven to be unfounded . This obThe investigation of POP requires close attention to detail and critical analysis of the time-line of events before and after anaphylaxis. This information should be extractable from the anesthetist's letter of referral and anesthetic charts. However, in view of the illegibility of hand-written charts, completion of a pro-forma template describing the reaction is particularly important. A suitable example is the referral template recommended by the Royal College of Anesthetists in the UK . The timIn view of the limited repertoire and sensitivity of currently available specific IgE assays, skin tests remain the most important investigatory tool for exploring the role of NMBs as a trigger for POP. Given the significant rate of background skin test positivity in the general population for many NMBs , its relDespite the high negative predictive value of skin tests, anaphylaxis has been rarely documented with NMBs chosen on the basis of negative skin tests , 44, thuThe principles underlying the use of drug provocation tests (DPT) in the investigation of POP are no different to that in any other area of drug allergy. Whilst supervised graded DPT are regarded as a gold standard in the diagnosis of drug allergy, these are not routinely undertaken in the context of general anesthetic drugs, to NMBs in particular. They can however, be considered in selected patients following a careful risk-benefit analysis, for antibiotics, opiates/opioids, chlorhexidine, latex and local anesthetic agents to narrow down on the list of possible culprits. The use of DPT in the investigation of suspected reactions to NMBs requires even more careful consideration because of the need to use the intravenous route and the greater risk of potentially fatal anaphylaxis as opposed to an oral DPT. For the vast majority of patients experiencing NMB-associated anaphylaxis, the identification of a safe alternative following skin testing allows these patients to be safely re-anesthetized. In those rare instances where patients are skin test positive to all NMBs tested, it may be necessary to undertake an intravenous DPT in an experienced unit in an intensive care or anesthetic setting. However, it is important to emphasize the lack of consensus on undertaking DPT for NMB agents. Guidelines from ENDA/EAACI and the French Society for Intensive Care (SFAR) do not recommend performance of DPT for NMB agents . More reTesting for specific IgE to complement but not as a substitute for skin tests is of value to a limited range of drugs. For antibiotics, drug-specific IgE assays are limited to the major and minor determinants (Penicillin V and Penicillin G) of penicillin, amoxicillin and ampicillin . These tWhile specific IgE assays to various NMB  are available, widespread use has been hampered by the lack of systematic validation and variation in sensitivity (38.5–92%) and specificity (85.7–100%) . The utiex-vivo activation by the suspected drug is a promising technique but exhibits lower sensitivity in comparison with skin tests for NMBs  by detection of upregulated membrane markers  in response to for NMBs . Whetherfor NMBs . This vifor NMBs .The optimal timing of investigations following an episode of POP has been the subject of debate. Based on a theoretical concern that skin testing immediately after the event may result in false-negative results due to consumption of specific IgE and mast cell refractoriness, some guidelines recommend that drug allergy investigation are performed at least 4–6 weeks after the event , 54. In The limitations of currently available tools for drug allergy investigation results in a failure to identify a clear trigger in a substantial proportion of patients with POP –10. The Auditing the outcome of repeat anesthesia following drug allergy investigation provides quality assurance of investigatory methods and represents good clinical governance. Based on a small number of studies, the rate of repeat anaphylaxis following an index episode is estimated at 1–4% . The emeThis review has highlighted the high stakes surrounding the investigation of peri-operative anaphylaxis and the frequent need to make recommendations based on imperfect data. Despite the limitations of drug allergy testing, it is absolutely vital that all patients with suspected POP undergo thorough investigation to avoid the morbidity and mortality associated with repeat episodes of avoidable anaphylaxis. Failure to investigate does result in repeat episodes  and carrInvestigations should be restricted to specialist allergy centers with appropriate knowledge, skill and experience in the investigation and management of drug allergy. Subject to substantial future advances in the investigatory tools available, the investigation of peri-operative anaphylaxis will remain dependent on clear documentation by anesthetists, obtaining a clear time-line of events, judicious use of skin tests and allergen-specific IgE and the exercise of astute clinical judgement.SAM was lead author of the manuscript and was responsible for planning and writing the paper. MTK critically reviewed and co-authored the paper.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.


Inner ear hair cells are mechanosensory receptors that perceive mechanical sound and help to decode the sound in order to understand spoken language. Exposure to intense noise may result in the damage to the inner ear hair cells, causing noise-induced hearing loss (NIHL). Particularly, the outer hair cells are the first and the most affected cells in NIHL. After acoustic trauma, hair cells lose their structural integrity and initiate a self-deterioration process due to the oxidative stress. The activation of different cellular death pathways leads to complete hair cell death. This review specifically presents the current understanding of the mechanism exists behind the loss of inner ear hair cell in the auditory portion after noise-induced trauma. The article also explains the recent hair cell protection strategies to prevent the damage and restore hearing function in mammals. The inner ear is the most incredible and sophisticated organ of the body. It connects the personnel with the outer world in the form of hearing. The hearing loss is referred to as the most common sensory disorder that affects all age groups of the world population. The complex architecture of the mammalian organ of Corti makes it more susceptible to damage and is difficult to revert back into its native form , 2. AlthSensorineural hearing loss (SNHL) is referred to as the most common type of hearing disorder occurs due to the damage or loss of the hair cells, the neuron-hair cell synapses, and/or degeneration of neurons. The SNHL is not completely recoverable due to the lack of self-regenerative capacity of HCs and SGNs. The patients having SNHL may be provided with the hearing aids, and in case of severe to profound hearing loss, the patients have the only option of cochlear implants . HoweverThere are multiple etiologies of SNHL. At any age, the foremost reasons for hearing loss are genetic and the environmental factors. The main causes of SNHL are degenerative processes associated with aging, gene mutations, noise exposure, and the use of therapeutic drugs that have ototoxic side effects –16. InteStereociliary bundles found on the surface of hair cells are more susceptible to mechanical damage. The exposure to intense noise causes direct mechanical disruption of stereociliary structure and disrupts the normal cellular organization of the organ of Corti –24. Howeα (TNF-α) [The reactive oxygen species (ROS) are observed in the hair cells after the acoustic overexposure and exist there for about 10 days . The ROS (TNF-α) , 38.N-terminal kinase (JNK)/mitogen-activated protein kinase (MAPK) also induces a mitochondrial cell death pathway through the stimulation and translocation of Bax and procaspases, release of cytochrome c from mitochondria into the damage cell cytoplasm, and lastly, the cleavage of fodrin by activating caspases [α and interleukin 1β were upregulated by the microglia, fibrocytes, and neuronal cells at different time points in the noise-exposed cochlea [Two complex signaling pathways are commonly involved in noise-induced hair cell loss that are known as intrinsic and extrinsic cell death signaling pathways. In the cochlea exposed to intense noise, the extracellular stimuli initiate the extrinsic cell death signaling pathway by inducing the transmembrane death receptors. These receptors activate the caspase 8, which further triggers the distinct downstream signaling pathway leading to the activation of caspase 3 that mediates apoptosis in the outer hair cells . The intcaspases . A recen cochlea  suggestiα (TNF-α) pathway has also been activated in the noise-induced damage model [Caspase-independent apoptotic pathway is also involved in the hair cell loss. After the exposure to loud noise, the mitochondria participate in the apoptosis by releasing the apoptosis-inducing factors (AIFs) and endonuclease G (EndoG) through the outer mitochondrial membrane into the hair cell cytoplasm. EndoG translocates to cell nucleus in order to initiate apoptosis while the AIFs may not directly be involved in apoptosis but act as a redox factor in return to noise-induced oxidative stress . Howeverge model ; howeverge model .The acoustic overexposure results in an increase accumulation of free calcium ions in the outer hair cells that enter through the L-type calcium channels and cell intracellular stores such as the mitochondria and endoplasmic reticulum , 48. TheThese studies highlight the possible mechanisms of hair cell loss in a noise-induced cochlear damage model. Besides the fact that the oxidative stress and the activated death pathways after acoustic overexposure detrimentally affect the cochlea, it takes a longer duration to degenerate hair cells after acoustic injury, suggesting that there is a possibility to interrupt this diminishing process in the mammalian cochlea.Genetic factors may contribute to the development of noise-induced hearing loss. The individual humans and animals displayed a variation in the susceptibility to noise-induced damage even under controlled conditions. This difference in susceptibility may be influenced by the genetic factors. For the last two decades, several genetic studies were performed to identify the NIHL susceptibility genes and among them various NIHL susceptibility genes have been known to involved in different cellular pathways such as the genes involved in the potassium recycling pathway  , 52, oxiApart from this, recent studies also highlight that the synapse degeneration in the inner ear is another key contributor of NIHL. The synapsis between the inner hair cells and spiral ganglion neurons is more prone to cellular damage . GlutamaVarious strategies have been defined to protect inner ear hair cells from acoustic damage. Some of the useful external protective measures are to reduce the exposure of loud noise by eliminating the basic source of the noise. However, it is not possible to take this measure in all the conditions, particularly in the areas of high noise pollution such as in the industrial world. Therefore, the use of hearing protection devices is recommended and in somewhat effective to reduce the acoustic damage. Multiple studies have suggested the use of hearing protection devices that significantly reduce the loud noise exposure, thus minimizing the risk of hearing loss in the industrial workers –74. HoweBesides the external measures of hearing protection, the otoprotective treatment on a cellular level is mainly focused for the prevention of hair cell loss and induction of the self-repair mechanism to restore auditory function. The most effective strategies used to prevent hair cell loss after noise-induced damage are: (1) use of antioxidants, (2) inhibition of programmed cell death pathways, (3) anti-inflammatory therapies, and (4) neurotrophic factors.tert-butylnitrone (4-OHPBN) and N-acetyl-L-cysteine (NAC) after acoustic overexposure significantly reduces the noise-induced hearing loss [tert-butylnitrone and NAC) in combination that also protected the hair cells and afferent neurites from noise-induced damage and preserved the cochlear structural components [Antioxidants are the potential therapeutics used to protect inner ear hair cells from acoustic damage. The oral administration of antioxidant drugs such as 4-hydroxy-alpha-phenyl-ing loss . Anothermponents . In addimponents –81. Simimponents –84. The mponents –84. Howemponents . Kopke emponents . Collectmponents , coenzymmponents , resveramponents , glutathmponents , ginsengmponents , D-methimponents , and vitmponents –95. The mponents , 97. TheManipulation of intrinsic cell death cascades using different antiapoptotic inhibitors is also a promising strategy to protect hair cells after the noise-induced hearing loss. Multiple studies have shown the activation of MAPK/JNK pathways in cellular stress response. The blocking of this pathway using the JNK inhibitory molecules in the animal model provides significant protection against the acoustic trauma , 99. SimSeveral types of anti-inflammatory drugs have been reported to rescue the hearing deterioration in the inner ear induced by the sound overexposure. Particularly, the use of steroids such as dexamethasone and dehydroepiandrosterone reduces the noise-induced trauma in the guinea pig and mice models –107. TheAlthough the neurotrophins are the key regulators for differentiation, survival, and maintenance of neuronal cells, several studies have reported their otoprotective role against the noise-induced hearing loss –113. NeuIt is very fascinating to observe that several strategies and drugs have been discovered to protect the inner ear hair cells from acoustic damage. A common strategy in recent years appears to target and manipulate the programmed cell death pathways and involves the use of antioxidants to control the oxidative stress in hair cells. After noise-induced ototoxic damage, there are different signaling pathways activated in the cochlea that induce hair cell death. The interruption in one of these death signaling cascades by specific inhibitor might not be that effective to rescue the auditory function until the multiple drugs or molecular inhibitors are not used in combination. The cellular cascades are interlinked with each other, and there is a possibility that the inhibition of one pathway with specific inhibitor might result in the activation of other cell death pathways in hair cells. Thus, a synergistic approach would be more beneficial to restore the hearing loss.As reviewed above, to study the noise-induced hearing loss in the animal model, the researchers used various approaches such as different animal species, sound intensity, frequency spectrum, and continuous or impulse noise. This sometime creates a conflict among the results of some drug studies that have found to be otoprotective by one group while reported as ineffective by the other group. The most probable reason for these conflicts is the difference between genetic backgrounds of different animal species that have different sensitivities to intense sound; thus, there is a possibility for different responses of same drug in different animal models. It is important to understand that the majority of animal studies showed a statistically significant impact when the protective drug reduces the hearing loss by 2-3 decibels (dB). However, in humans, this shift should be more than 10 dB to be effective for the auditory performance, and the hearing below this level may have a very less impact on person hearing capability. Therefore, in the future, it is important to first perform the otoprotective therapeutic experiments in different animal models with different acoustic exposure conditions before taking it into the clinical trials.In recent years, research on the noise-induced hearing loss is focused in order to develop various therapeutic strategies for appropriate protection of hair cells from any damage and to restore the auditory function after acoustic trauma. The momentum builts up by these studies on the effectiveness of different otoprotective agents such as the antioxidants, anti-inflammatory agents, and neurotrophic factors, and manipulation of the intrinsic cell death pathways in hair cells will likely drive the complete development of therapeutic interventions for restoring the noise-induced hearing loss in the future. However, identification of the optimal conditions such as the dose regimen, effective route of administration, and timings for new drugs and their synergistic plans to treat sound-induced hearing loss in patients is important to be focused in the future experiments.


Systemic lupus erythematosus (SLE) is an autoimmune disease with a wide range of clinical manifestations. Cognitive dysfunction is one of the manifestations that could present prior to the emergence of any other neuropsychiatric involvements in SLE. Cognitive dysfunction is a subtle condition occurring with a high frequency. However, there is no data on the correlation of cognitive dysfunction with central nervous system (CNS) imaging findings, in particular single-photon emission computed tomography scan (SPECT) and functional MRI. We decided to perform a systematic review of brain SPECT and fMRI in SLE patients with cognitive dysfunction. PubMed, Scopus, and Google Scholar databases were searched until April 2017 with the following keywords: “SLE OR systemic lupus erythematous OR lupus” AND “functional MRI OR functional magnetic resonance imaging OR fMRI OR SPECT or SCAN”. A total of 1,767articles were found. Two rheumatologists reviewed the articles and finally 14 articles were selected for the final systematic review. The fMRI and SPECT imaging techniques could provide valuable information regarding the SLE patients with cognitive dysfunction at the early stages of the disease. Brain SPECT scan and fMRI are used as functional imaging tools in SLE. Both of these diagnostic modalities are sensitive in reflecting the subtle brain damages in SLE patients with cognitive dysfunction. Brain fMRI and SPECT scan could be significantly beneficial in the diagnosis and initial management of cognitive dysfunction in SLE. Nevertheless, prospective studies could be useful in confirming the application of these diagnostic modalities in the clinical setting. Among different neuropsychiatric manifestations of systemic lupus erythematosus (SLE), cognitive dysfunction has recently gained specific attention. Cognitive dysfunction is one of the inconspicuous manifestations of SLE that involves the central nervous system (CNS). A myriad of neuropsychiatric syndromes may occur at any time during the course of the disease. The patients inflicted with neuropsychiatric SLE (NP-SLE) usually complain of having problems in memory and executive skills such as attention, visual-spatial function, verbal fluency, motor function as well as planning, organizing, and sequencing information. The first study that investigated cognitive impairment in SLE patients reported a prevalence rate of 66% for this dysfunction among SLE patients. Cognitive dysfunction is the most common psychiatric manifestations of SLE, which is reported in up to 80% of SLE cases . It is oCognitive impairment in NP-SLE shows a strong relationship with hippocampal atrophy, which can be caused by autoantibodies , cytokinVarious brain pathologies may primarily represent as functional changes, preceding the anatomical changes. The brain SPECT provides three-dimensional (3D) functional information using a single gamma ray emission in addition to the injection of trace amounts of molecules labeled with a radioactive isotope. There are several studies indicating a correlation between disease activity and brain abnormalities on the SPECT in the parietal, frontal, and temporal lobes , 8.Brain hypoperfusion in SLE may represent reversible lesions or subclinical CNS involvement. The SPECT imaging seems to be useful in detecting and monitoring CNS involvement in SLE. The fMRI is an MRI method that can detect brain functional impairments according to the changes in parenchymal perfusion. This technique is based on the relationship between neuronal function and blood flow. The fMRI can detect subtle alterations in brain perfusion occurring when the patient performs a task called paradigm. The standard technique for fMRI is based on the blood-oxygen-level dependence imaging that is based on the delicate autoregulatory mechanisms of the blood flow in the brain upon the activation of a brain area. In this regard, when an area in the brain is activated, the neuronal metabolism and oxygen consumption are increased. This initially leads to the elevation of deoxyhemoglobin concentration. After a gap of 2-6 sec, the autoregulation leads to the enhancement of the blood flow to the area, followed by the enhancement of oxyhemoglobin concentration. This oxyhemoglobin concentration makes the signal used in the fMRI for image acquisition.Given the importance and high frequency of cognitive dysfunction, it seems essential to establish objective methods for the evaluation of cognitive problems in SLE. With this background in mind, the present systematic review was conducted to investigate the diagnostic value of fMRI and SPECT in SLE patients with cognitive dysfunction.Literature search strategyAn electronic literature review was conducted on the studies published until April 2017 in several databases including PubMed, Scopus, and Google Scholar. The searching process was performed using the following keywords: “SLE OR systemic lupus erythematous OR lupus” AND “functional MRI OR fMRI OR SPECT”. Any discrepancy between the electronic records was noted and resolved subsequently. In addition, all references of the selected articles were manually searched to find possible related articles. All peer-reviewed articles published in English and evaluated cognitive dysfunction in SLE patients by brain fMRI and/or brain SPECT was included. In addition, all different types of articles with various study designs including clinical trials, case-controls, cross-sectional research studies, cohort studies, and case series were eligible to be included.The quality of the articles was assessed by the Oxford Center for Evidence-Based Medicine Checklist for diagnostic investigations . The selThe SLE was defined using the 1982 ACR criteria  and cognThe final decision was made to exclude the studies that contained the following criteria:1. Inaccessible articles which could not be obtained by sending emails to the corresponding authors2. A sample size of less than five patients3. Conference papers and letters to the editor, review articles, and meta-analysis 4. Animal studies Study selectionThe initial study selection was made based on the titles and, where available, the abstracts in case of meeting the inclusion criteria. Subsequently, the full-text versions were obtained for the further assessment of the studies. The identification and removal of the duplicated references were performed in the next step. Some studies were added manually. All human studies were included without any age limitation. A total of 1,767articles published until 2017 were collected based on their titles. Four additional articles were included by manually searching the reference lists of the previously selected papers. The title and abstract review resulted in the exclusion of 359 publications because animals were investigated. We included the articles that only evaluated the NP-SLE patients with cognitive dysfunction. Therefore, out of the remained titles, 14 potentially relevant publications were entered into the study after performing a step by step evaluation of the full-texts. The quality assessment of the included studies is presented in Data analysisThe evaluation of the articles was performed by two rheumatologists who appraised the selected articles independently. All available and necessary information, including the name of the first author, country and year of publication, sample size, intervention , and main findings were extracted. The third author was engaged in the data extraction process if needed. Due to the heterogeneity of the studies, a meta-analysis could not be performed in this review.The summarized findings of the fourteen articles included in the final review are presented in Shapira-Lichter et al. evaluated SLE patients without overt NP-SLE and reported that 3 out of 12 SLE patients suffered from cognitive dysfunction, including difficulty in remembering names and words . The revCognitive dysfunction is an important neuropsychiatric manifestation in SLE. It is difficult to diagnose cognitive dysfunction secondary to pure brain involvement in SLE patients due to insufficient knowledge of the exact pathophysiology and lack of approved standard objective tests. The current systematic review was focused on the studies utilizing brain fMRI and SPECT techniques for the assessment of cognitive dysfunction in SLE.Brain single-photon emission computed tomography scan (SPECT)In a study conducted by Driver et al. on 37 SLE patients with cognitive dysfunction, only seven patients were reported to have normal brain SPECT scans . The patients with severe cognitive dysfunction had more severe perfusion deficits in the watershed areas of the bilateral frontal lobes compared to those with mild ones . In a study performed by Oh et al., brain SPECT scan facilitated the detection of a significant hypoperfusion in the right precuneus in SLE patients with memory impairment. Accordingly, they concluded that the analysis of the statistical parametric mapping of the brain SPECT could be a beneficial tool to evaluate the regional cerebral blood flow (rCBF) in SLE patients with memory impairment .Nishimura et al. revealed an association between the neurocognitive impairment (NCI) and general SLE activity. The dominant pattern of NCI involves reduced psychomotor speed and notable deficits in attention, information processing, learning, memory, and executive function . It was Waterloo stated that none of the cognitive dysfunction domains were associated with regional or global CBF observed on brain SPECT scan. In addition, cerebral infarcts detected by MRI were associated with cognitive dysfunction . Maeshim99mTc hexamethyl-propylene-aminoxime (HMPAO) SPECT studies can be performed before and after methylprednisolone pulse therapy in NP-SLE patients. This technique might play an important role in determination of the effects of pulse therapy on rCBF (99mTc ethyl cysteinate dimer (ECD) brain SPECT in determination of rCBF changes after methylprednisolone pulse therapy The evaluation of fMRI findings in patients with NP-SLE demonstrated a higher normal-appearing white matter fractional anisotropy histogram peak height and more significant activations of the putamen, dentate nuclei, and primary sensorimotor cortex contralaterally . DiffereIn a study conducted by DiFrancesco et al., the MRI data revealed a greater activation in the hippocampus and prefrontal regions among SLE children with cognitive dysfunction . FurtherCesar et al. reported that patients with NP-SLE experience showed a considerable reduction in the white matter tract integrity. However, the decreased auditory-verbal memory was not associated with changes in the white matter integrity among these patients. In the mentioned study, the patients demonstrated increased number and volume of T2 lesion and enhanced lesion attenuation in the left superior and a small portion of the right posterior corona radiata .Language deficit is one of the earliest deficiencies developing in neurological conditions. The prototypic language areas in the brain are Broca’s and Wernike’s areas, both of which are impaired in non-symptomatic SLE patients . In thisMemory function is a complex entity, which involves many different brain areas. DiFrancesco et al. showed the greater activation of the hippocampus and prefrontal regions in SLE patients. This finding suggests the impairment of the areas associated with memory in these patients. They also suggested that impairment in the visual and attention areas mandates the memory task and makes the paradigm more impaired .Fitzgibbon et al. also evaluated memory task and showed the greater activation of the frontoparietal regions. They hypothesized that these changes might be due to the impairment of the white matter circuits needed in memory task resulting in the generation of new pathways . Mackay In another study performed by Piga et al., it was shown that SLE patients with and without NP-SLE had a significant brain damage progression which was associated with deterioration of the white matter hyperintensities, brain volume loss, and occurrence of new cortical parenchymal defects. Therefore, MRI-diagnosed brain damages are associated with a higher risk of developing neuropsychiatric manifestations . InconsiThe cingulate gyrus performs an inhibitory function . DiFrancThe brain diagnostic modalities including SPECT scan and fMRI are sensitive in the diagnosis of subtle brain damages at early stages of cognitive dysfunction in SLE.


The aim of this study was to determine the effect of general rehabilitation gymnastics on subjective and objective characteristics of locomotor system in older women with chronic LBP. To satisfy this goal, the outcomes in exercising women were compared with the results of nonexercising controls. The study group included 21 women with chronic LBP (age 65-75 years), participating in a 3-year general rehabilitation program combining strength, stretching, endurance, balance, and stabilization exercises with Muscle Energy Techniques (MET). Control group included 20 women with chronic LBP, who neither undertook the gymnastics nor participated in other forms of physical activity. The list of outcome measures included pain severity , limitations in the activities of daily living (Oswestry Disability Index and Roland-Morris Disability Questionnaire), mobility of all spinal segments (tensometric electrogoniometry), and bioelectrical activity of back muscles (kinesiologic electromyography). Exercising women presented with lesser severity of current pain  and pain experienced during the last three months , reported less ailments during the last three months, and had fewer limitations in the activities of daily living  than the controls. Moreover, they showed significantly higher values of nearly all spondylometric parameters except for cervical lateral flexion. The study groups did not differ in the amplitudes of bioelectrical signal from the back muscles. These findings may point to beneficial effects of the combined exercise program. The most common musculoskeletal disorder found in this age group is low back pain (LBP) . LBP is LBP is defined as pain in the back from the level of the lowest rib down to the gluteal fold . The paiPublished evidence suggests that there is a link between muscle weakness, low physical activity, and increased risk of back pain , 11. ManThe aim of this study was to analyze the effects of general rehabilitation gymnastics program with various types of exercises on the subjective and objective indices of locomotor system status in older women with chronic LBP. To satisfy this goal, we compared the outcomes in women who participated in the general rehabilitation gymnastics program with the results of nonexercising controls.The study included 21 women between 65 and 75 years of age, who participated in a 3-year biweekly general rehabilitation gymnastics program at “Antidotum” NFZ Rehabilitation Center. Aside from the gymnastics, the study subjects did not undertake any other forms of physical activity. Control group was comprised of 20 women between 65 and 75 years of age, who did not practice general rehabilitation gymnastics and other forms of sport or recreational physical activity. The selection of women participating in the study was conditioned by meeting specific conditions. The research group consisted of 21 out of 38 women, who during the period of 3 years have regularly participated general rehabilitation gymnastics program with the elements of Muscle Energy Techniques (MET). The program was conducted by a physiotherapist specializing in this method. The control group consisted of women who were enrolled to “Antidotum” NFZ Rehabilitation Center (N=86). They were chosen before starting rehabilitation based on their responses to the initial medical interview.Selection of women to both study groups was based on a detailed and thorough analysis of clinical and demographic criteria. The list of demographic criteria included age, place of residence, economic status and education. Both groups included solely women aged between 65 and 75 years of age, inhabitants of Stęszew county , with moderate or high economic status and secondary or higher education. Detailed information about the participant flow to both study groups is presented in A clinical inclusion criterion to the study groups was presence of a chronic lower back pain (CLBP) persisting for more than three months. Lower back pain was defined as a unilateral or bilateral pain the intensity of which changed depending on body position and time of the day), located between the level of the lowest (XII) rib down and the gluteal fold. Also women with concomitant pain in one or both buttocks were eligible for the study. Presence of a concomitant pain/numbness/muscle weakness in one or both lower extremities, suggestive of disc-root conflict, was a considered a clinical exclusion criterion. Another exclusion criterion was occurrence of a persistent pain the intensity of which did not change depending on body position and time of the day. Also women with concomitant pain in cervical and/or thoracic spine were not qualified to the study. Finally, a present or past history of gross pathologies, e.g., osteoporosis, spinal infections, neoplasms, cauda equina syndrome, spinal fractures, or surgeries, disqualified from participation in the study.Detailed characteristics of the study participants are presented in General rehabilitation gymnastics sessions took place twice a week and lasted 45 min each. The intensity of the exercise was moderate. The program included strength, endurance, stretching, balance and stabilization exercises. The subjects performed bodyweight resistance exercises and exercises with Thera-Band resistance bands . The aim of the resistance training was to strengthen some specific muscle groups, such as erector spinae muscles, rectus abdominis muscle, abdominal internal and external oblique muscles, transverse abdominal muscle, deltoid muscle, triceps brachii muscle, biceps brachii muscle, rhomboid muscle, serratus anterior muscle, infraspinatus muscle, teres minor muscle, quadriceps femoris muscle, gluteal muscles , tibialis anterior muscle, and flexor digitorum longus muscle. During the resistance training, subjects performed isometric, concentric, and eccentric muscle work. The stretching exercises involved primarily trapezius muscle (descending part), scalene muscles , sternocleidomastoid muscle, pectoralis major muscle, latissimus dorsi muscle, teres major muscle, suboccipital muscle, spinal rotators and erector spinae muscles , ischiocrural muscles (hamstring), rectus abdominis muscle, piriformis muscle, and triceps surae muscle. The stretching exercises included the elements of MET, such as Contact Relax (CR) and Contract-Relax-Contract (CRC) techniques based on neurophysiological mechanisms of postisometric relaxation and reciprocal inhibition . Each stSelected characteristics of women from the exercising and nonexercising group were determined with objective and subjective methods. Both subjective and objective methods were conducted by a blinded assessor.Tensometric Electrogoniometry. Spinal mobility was determined with Penny & Giles tensometric electrogoniometer in Boocock modification [fication . The meafication , with twfication . The mobSurface Electromyography (EMG). Kinesiologic electromyography was carried out with an 8-channel electromyographic system with plate electrodes . The results were recorded using DataLog Bluetooth V7.5 software (Biometrics Ltd). During the examination, two multiple-use surface electrodes (type SX230 1000) were attached with an adhesive tape, after removal of body hair from a 2 cm x 1 cm area of intact skin, disinfection of electrode surface, and wiping the skin a few times with salicylic alcohol to reduce its resistance. The reference electrode  was fixed at the distal end of the radius (Lister's tubercle region) with an elastic band. The examination involved lumbar segment of the longissimus muscle, both right- and left-sided bundles. The electrodes were placed according to the international guidelines published by SENIAM [y SENIAM . The exaThe list of determined electromyographic parameters included the amplitude of bioelectrical signal from the longissimus muscle, expressed in microvolt. Avoiding a confounding effect associated with measurement conditions, the results were normalized to a reference Maximum Voluntary Contraction (MVC) and expressed in percent . After fThen, the subject was examined during standing up from a chair, sitting down on a chair, lifting up and putting down a 2 kg rehabilitation roller. Each test was conducted at an individually-adjusted pace, and included three repetitions with 30-second intervals in between. The test started on the examiner's command. Lifting up and putting down the rehabilitation roller, the subjects kept their back straight and flexed their hips. The result of each test was presented as the mean amplitude for the three repetitions, either for the whole muscle or for its right- and left-sided bundles. The results were normalized to MVC, to estimate the degree of the muscle involvement during various activities  in relation to maximum neuromuscular activation. To provide accurate results, appropriateness of each electrode's placement was re-checked prior to each repetition.Revised Oswestry Pain Questionnaire. The degree of LBP-imposed limitations in ADLs was determined with Revised Oswestry Pain Questionnaire, also referred to as Oswestry Disability Index (ODI). We used this specific modification of the questionnaire, since unlike other instruments, it included a question about changes in lumbar pain intensity. The survey consisted of 10 questions, each with 6 possible responses scored from 0 to 5 points. If the respondent chose more than one answer to a given question, the one with higher score was recorded and subjected to the analysis. Maximum overall score amounted to 50 points, which corresponded to 100% disability due to lumbar pain [bar pain . Mistersbar pain . Cronbacbar pain .Roland-Morris Disability Questionnaire (RMDQ). The second most commonly used questionnaire for the determination of disability associated with lumbar pain is Roland-Morris Disability Questionnaire (RMDQ). The instrument consists of 24 statements about pain and its influence on ADLs. The respondent chooses only the statements that refer to his/her ailments. Maximum overall score may vary between 0 and 24 points. Polish adaptation of RMDQ was prepared by Opara et al. [a et al. . Cronbaca et al. . RMDQ isa et al. .Numeric Rating Scale (NRS). NRS is a most common instrument to assess the severity of a given ailment. It describes subjective intensity of pain on a scale from 0 (no pain) to 10 (worst possible pain). Research showed that NRS and Visual Analog Scale are highly accurate, reliable, and reproducible instruments to determine pain intensity [ntensity . In our The results  were recorded in MS Excel 97-2003 database and subjected to statistical analysis with Statistica package, version 13 (StatSoft).The methods of mathematical statistics used to analyze the data included Student t-test to verify the significance of differences between two variables and Snedecor's F-test to examine the significance of between-group differences in the values of dependent variables.To identify the parameters which were influenced most by participation in the general rehabilitation gymnastics program, partial eta-squared values were calculated as an effect measure. The higher the partial eta-squared value, the greater the contribution of the gymnastics to differences in a given parameter between exercising and nonexercising women. A relationship between the bioelectrical activity of the longissimus muscle during various activities and 100% neuromuscular activation of this muscle  was determined on multiple regression analysis.The results were presented graphically, as the charts and plots of various types.Prior to the study, all women enrolled to the project were informed about its objectives, protocol and methods, and were assured that all the study procedures were noninvasive and safe. Participation in the study was voluntary and free of charge. The participants had the right to withdraw from the study at any time. Moreover, they were assured that before processing, their data will be fully anonymized, and the study results will be used solely for the research purposes, which they consented to. The study included solely the women who gave their written informed consent to participate in the project.The protocol of the study was approved by the Local Bioethics Committee at the Poznan University of Medical Sciences (decision no. 899/17).We compared somatic traits (body height and body weight) and BMI of exercising women and nonexercising controls see . Test ofTo analyze the effects of general rehabilitation gymnastics on the ability of the study subjects to undertake ADLs and the intensity of pain caused by chronic LBP, we used three subjective instruments: Revised Oswestry Pain Questionnaire, Roland-Morris Disability Questionnaire, and Numeric Rating Scale (NRS). The results for exercising women and nonexercising controls are presented in Analysis of variance demonstrated significant differences in mean scores for exercising and nonexercising women see . Women wWe also analyzed the effect of general rehabilitation gymnastics (various types of exercises combined with MET) on functional parameters of the spine in women with LBP. To satisfy this objective, we compared spinal mobility in frontal, transverse and sagittal plane in exercising and nonexercising women. Women who participated in the general rehabilitation gymnastics program presented with significantly higher values of all spondylometric parameters. The results are presented on We used partial eta-squared values to identify the spondylometric parameter that was influenced most by the general rehabilitation gymnastic factor see . The higAnother aim of this study was to analyze the effect of general rehabilitation gymnastics on bioelectrical activity of muscles stabilizing lumbar spine. To satisfy this objective, we compared bioelectrical activity of lumbar portion of the longissimus muscle and its right- and left-sided bundles during various activities undertaken by exercising and nonexercising women.R and MVCL+R (see R) and for the whole muscle (MVCL+R) in exercising women imply that general rehabilitation gymnastics exerted a beneficial effect on the strength of muscles stabilizing lumbar spine. Based on partial eta-squared values it can be concluded that general rehabilitation gymnastics contributed to 10% between group variance in MVCR values in exercising and nonexercising women , sitting down on a chair (Sd), and lifting up (Lu) and putting down a rehabilitation roller (Pd). Mean activation amplitude during each of these activities was calculated for the whole longissimus muscle and for its right- and left-sided bundles. Although exercising women presented with higher values of all parameters, analysis of variance demonstrated statistically significant between group differences solely for MVCCL+R see . Signifiomen see .L+R, SdL+R, LuL+R, and PdL+R) explained 51% of variance in the dependent variable (MVCL+R) in exercising women (coefficient of determination = multiple R2 = 0.509 x100) and 41% in nonexercising women (coefficient of determination = multiple R2 = 0.413 x100) . Four independent variables included in the model (Gu100) see . The res100) see . ProbablSubsequently, the amplitudes of the longissimus activation during various activities were divided by the respective MVC values, both for the whole muscle and for its right- and left-sided bundles. As a result, the degree of neuromuscular activation during various activities was expressed as the percentage of MVC see . The relChronic lower back pain frequently contributes to worse comfort of life in the elderly since strong pain causes serious limitations in the activities of daily living. This makes the topic of this study of utmost importance. A serious limitation of our study was its retrospective character. Nevertheless, the study had also some strengths among which the most important is relatively large size and homogeneity of the study group. The study included older women, aged 65-75 years, who participated in a 3-year general rehabilitation gymnastics program combining strength, stretching, endurance, balance and stabilization exercises with the elements of Muscle Energy Techniques, supervised by the same physiotherapist, a specialist in MET. To the best of our knowledge, the outcome of such complex therapy  has not been a subject of any previously published study. This highlights the value of our study, conducted in a group of patients who are generally difficult to access. The lack of baseline measurements resulted from the inability to access the exercising women at the time of their enrollment to the gymnastics program. We were able to examine the women no earlier than after three years of a regular exercising. Hence, we decided to compare the results obtained in the exercising group with the results of nonexercising women who presented with the same ailments. Selection of women to both study groups was based on a detailed and thorough analysis. Considering the number of study eligibility criteria, the examined sample can be considered large enough, and in our opinion, the results obtained in such group are sufficient to formulate conclusions important from the practitioner's perspective. et al. studied the effects of “aggressive physical conditioning” in older persons [ et al. examined the effects of a 6-week spine rehabilitation program for older persons, including a combination of strength, stretching and endurance exercises [ et al. conducted a randomized controlled trial including a group of 200 older persons, to verify the effectiveness of general conditioning and aerobic exercises on a treadmill or cycling ergometer, combined with percutaneous electrical nerve stimulation [Previous studies analyzed effectiveness of various combined exercise programs in attenuation of pain experienced by older persons with chronic LBP. For example, Khalil persons . Their txercises . In addimulation . Aside fmulation . Accordimulation . Howevermulation .max values amounted to 31.3%.Our study demonstrated that participation in a 3-year training program combining general rehabilitation gymnastics  with elements of MET, divided into 45-min biweekly sessions, contributed to a statistically significant reduction of pain severity  in older women (65-75 years of age) with chronic LBP. At the end of the training program, the level of pain in participating women was 62.4% lower than in nonexercising controls, and the between group difference in NRSSuch evident difference in the severity of pain reported by women who engaged in general rehabilitation gymnastics and those who did not, implies that participation in the training might attenuate pain in older persons with chronic LBP. Probably, these were the elements of MET which added considerably to the outcome of the program; the beneficial role of MET in pain attenuation has been already demonstrated by other authors , 29.A statistically significant effect (p<0.05) of nonpharmacological interventions on the severity of chronic pain in older patients was also demonstrated by Park et al. . ReductiPain associated with LBP imposes limitations on ADLs . A few pWomen with chronic LBP who participated in our training program presented with lower ODI and RMDQ scores than the controls, by 30% and 65%, respectively; this implies that the exercising women experienced less pain-imposed limitations in ADLs. In our opinion, the substantial difference in the results obtained with the two questionnaires was associated with the fact that they referred to various areas of daily living. This suggests that the degree of disability due to chronic LBP should be assessed with a few various instruments. Irrespective of used questionnaire, the scores for women who participated in the exercise program were significantly different than in the controls, which is consistent with the results reported by other authors. According to Geneen et al., physical activity may contribute to a lesser pain and greater functional improvement not only in the case of LBP . Those aChronic LBP contributes to a considerable reduction of spine mobility in the affected person. The loss of spinal mobility is likely a consequence of degenerative changes in intervertebral discs . ImpaireIn our study, the range of spinal mobility was considerably greater in women who participated in the general rehabilitation gymnastics program than in the controls. The differences for nearly all analyzed parameters were statistically significant and observed regardless of spinal segment. Such substantial difference in the spondylometric parameters might reflect beneficial effect of the general rehabilitation gymnastics on motor function of the spine. The most evident between group difference was observed in the case of lumbar posterior flexion. Perhaps this was associated with the fact that prone lumbar extension was included in each training session and recommended as an exercise to be performed at home. Effectiveness of isolated lumbar extension in patients with chronic LBP was previously documented in a randomized controlled trial conducted by Steele et al. . The onlTo the best of our knowledge, none of the previous studies analyzed the effectiveness of combined exercises on spinal mobility in older persons with chronic LBP. Previous studies centered around the effects of isolated exercises. Helmhout et al. demonstrated that exercises for the erector spinae had beneficial effect on pain and functional disability in persons with chronic LBP, but did not improve lumbar mobility . BhadaurAside from general rehabilitation gymnastics, our training program included also elements of MET. These therapeutic procedures have been used frequently for the rehabilitation of virtually all body regions, in particular cervical and lumbar spine. Available evidence shows that MET may improve spinal mobility in persons with chronic LBP. Unfortunately, many of the studies dealing with the problem in question had some methodological flaws .Chronic LBP is postulated to play a significant role in the erector spinae dysfunction, which manifests as lower values of mean amplitude, mean density, and maximum amplitude for this muscle group in lumbar and thoracic region. Chronic LBP exerts the most detrimental effect on type I muscle fibers . A dysfuTo the best of our knowledge, none of the published studies analyzed the effects of combined exercises in patients with chronic LBP in the context of changes in bioelectrical activity of back muscles. Few papers dealing with the problem in question examined the outcomes of isolated interventions. A statistically significant (P < 0.05) change in muscle activity was observed in women with postpartum LBP, subjected to posteroanterior lumbar mobilization. Significantly lower surface EMG activity of the erector spinae might correspond to lesser ailments in this region . Also PoIn our study, we did not observe a significant difference in the bioelectrical activity of the longissimus dorsi muscle in women participating in general rehabilitation gymnastics program with elements of MET and in nonexercising controls. Perhaps, the lack of statistically significant between group differences might be a consequence of less demanding tasks used during EMG testing (standing up/seating down and lifting up/putting down a rehabilitation roller).Future studies should comprehensively evaluate the effectiveness of the complex therapy . Since CLBP is a common ailment, future research could be expanded onto various age groups of patients. Optimally, the problem in question should be a subject of a randomized clinical trial. An additional advantage of such study would be the possibility of a follow-up evaluation, to verify whether the beneficial effects of the therapy might persist longer.Older women with chronic LBP who participated in a general rehabilitation gymnastic program with the elements of muscle energy techniques (MET) presented with significantly lower pain, lesser limitations in the activities of daily living, and better spinal mobility. It can be assumed that the difference in the subjective and objective parameters of exercising and nonexercising women was a consequence of participation in the gymnastics program.The study groups did not differ significantly in terms of the amplitudes of bioelectrical signal from the back muscles, which might result from the use of a less burdensome EMG test .The following conclusions can be formulated based on the results of this study:


The development of immunotherapies has revolutionized intervention strategies for a variety of primary cancers. Despite this promising progress, treatment options for primary brain cancer and brain metastasis remain limited and still largely depend on surgical resection, radio- and/or chemotherapy. The paucity in the successful development of immunotherapies for brain cancers can in part be attributed to the traditional view of the brain as an immunologically privileged site. The presence of the blood-brain barrier and the absence of lymphatic drainage were believed to restrict the entry of blood-borne immune and inflammatory cells into the central nervous system (CNS), leading to an exclusion of the brain from systemic immune surveillance. However, recent insight from pre-clinical and clinical studies on the immune landscape of brain cancers challenged this dogma. Recruitment of blood-borne immune cells into the CNS provides unprecedented opportunities for the development of tumor microenvironment (TME)-targeted or immunotherapies against primary and metastatic cancers. Moreover, it is increasingly recognized that in addition to genotoxic effects, ionizing radiation represents a critical modulator of tumor-associated inflammation and synergizes with immunotherapies in adjuvant settings. This review summarizes current knowledge on the cellular and molecular identity of tumor-associated immune cells in primary and metastatic brain cancers and discusses underlying mechanisms by which ionizing radiation modulates the immune response. Detailed mechanistic insight into the effects of radiation on the unique immune landscape of brain cancers is essential for the development of multimodality intervention strategies in which immune-modulatory effects of radiotherapy are exploited to sensitize brain cancers to immunotherapies by converting immunologically “cold” into “hot” environments. Primary and metastatic brain tumors represent a challenging clinical issue. Glioblastoma (GBM) with an incidence of 2–3 per 100,000 population, is the most common primary brain tumor making up 54% of all gliomas and 16% of all primary brain tumors . Brain tThe primary goal of radiotherapy is the induction of DNA damage in rapidly dividing tumor cells to induce different forms of cell death such as apoptosis or mitotic catastrophe , 11. In Detailed understanding of the immune landscape of the central nervous system (CNS) at steady state and under pathological conditions is critical to appreciate immunological effects of radiotherapy in brain tumors. This review will therefore first summarize current knowledge on immune surveillance in the CNS and discuss how the development of primary and secondary brain tumors modulates the cellular composition of the TME and alters effector functions of tumor-associated immune cells. Based on this knowledge, different immunological aspects of brain tumors will be discussed to provide insight into the molecular basis of immunotherapy and radiotherapy in combination settings with a particular focus on differences in immune modulation depending on dose and fractionation of IR.The CNS has traditionally been regarded as an immune privileged site that is excluded from systemic immune surveillance . SeveralMoreover, a range of lymphoid cells including B- and T cells as well as innate lymphoid cells (ILC), natural killer (NK), and natural killer T (NKT) cells constitute the lymphoid compartment in the CNS . LymphocThe immune landscape in the CNS under steady state has recently been shown to be more complex than previously noted. Based on recent observations it was proposed to refer to the brain as an immunologically distinct rather than privileged site. Despite the description of the cellular constituents of the immune landscape in the CNS, it will be critical to evaluate to which extent the presence of lymphoid and myeloid cells in border-associated areas affects the immune privileged state of the brain parenchyma. In this regard, it is important to identify pathological stimuli that trigger infiltration of immune cells from border-associated areas as a route for immediate response or lead to recruitment of immune cells from the periphery and induction of a systemic response. There is accumulating evidence that different pathological conditions, including neurodegenerative disorders as well as cerebral cancers, induce fundamental changes in the cellular composition of the immune infiltrate and activation state of key players in neuro-inflammation . Importain vitro activated Pmel T cells  represent the most abundant stromal cell type in GBM and BrM often constituting up to 30% of the tumor mass , 45. Mic T cells . Imaging T cells . Moreove T cells . The aut T cells . T cell  T cells , indicat T cells –59. Immu T cells . Quantit T cells . It was  T cells . Moreove T cells , 64 or t T cells  at the t T cells . T cell  T cells . High le T cells . Tumor i T cells –73. Regu T cells , 74. Tum T cells , 75, 76.The immune landscape of BrM and its consequences on systemic and CNS immunity are less well-characterized compared to primary brain cancers. The question, if immune responses in BrM are predominately driven by the tissue environment or if the cellular identity of the tumor of origin  shapes the mode of inflammation, is currently a field of active research. In contrast to GBM, BrM show moderate or even pronounced T cell infiltration. Several studies reported that the extent and pattern of T cell infiltration depends on the primary tumor entity that metastasizes to the brain , 78. T cTaken together, thorough investigation of the tumor microenvironment in GBM and BrM indicate that brain cancers contain the cellular and molecular constituents for therapeutic intervention by checkpoint inhibition. However, clinical data revealed that checkpoint inhibitors as mono-therapy often fail to significantly improve survival rates , 86. A pThe current standard of care for newly diagnosed GBM is maximal surgical resection with concurrent radiotherapy and temozolomide (TMZ) chemotherapy followed by 6 months of adjuvant TMZ treatment . HoweverPrevious radiation regimen for brain metastasis patients involved whole brain radiotherapy (WBRT) with fractionated doses of 30 Gy in 10 fractions or 20 Gy in 5 fractions. Different clinical trials report a cerebral response following WBRT in 60% of patients and tumor volume reduction after WBRT has been associated with better neurocognitive function and prolonged survival . Median Given the dismal prognosis for GBM and BrM patients, in particular patients with recurrent GBM or patients with multiple BrM it is evident that improved intervention strategies are urgently needed to provide better care for brain cancer patients. The introduction of immunotherapy into the clinics for select cancer types led to new hope for an improved management of primary and metastatic brain cancers.Immune checkpoints are an important component of immune responses to keep cytotoxic activity of T cells under control to prevent autoimmunity. Cancers exploit this safety mechanism by up-regulation of checkpoint components on their cell surface to block T cell activity or by co-opting cells of the tumor microenvironment to establish an immune suppressive environment by dampening T cell responses. Checkpoint inhibitors unleash T cells from their inactive or exhausted state to induce anti-tumor responses  Figure . To dateAlthough multiple factors indicate that GBM harbors intrinsic resistance against checkpoint inhibition as mono-therapy, pre-clinical testing showed promising results . The CheIn sum, the extent of immune suppression that is established in GBM and BrM together with effects from standard of care treatment that further dampens immune responses might ultimately prevent effective immunotherapies. Therefore, it is important to develop improved intervention strategies that overcome current obstacles to successful immunotherapy in cerebral tumors. In addition to the recently initiated clinical trials that aim to test the efficacy of the combination of different checkpoint inhibitors, there is increasing interest in the potential synergy of radiotherapy and immunotherapy.Data from retrospective trials suggest that combinations of immunotherapy and radiotherapy significantly increase response rates and show effects on overall survival. For example, Knisely et al. reported that melanoma patients that received ipilimumab plus WBRT achieved longer median survival compared to WBRT alone [21.3 vs. 4.9 months] and a greater 2-year survival rate [47.2 vs. 19.7%] . SimilarIn sum, data from clinical and pre-clinical studies indicate that radiotherapy can act as a sensitizer for immunotherapy. Conventional fractionation takes advantage of the higher radio-sensitivity of tumor cells compared to normal cells with respect to DNA repair and cell cycle regulation. However, whether conventional fractionation represents the optimal strategy to maximize synergy with immunotherapy remains unclear to date. Moreover, it will be critical to evaluate whether radiation dose and fractionation that is optimal to induce an immune response in the CNS, is tolerated by the sensitive brain tissue. In order to optimize radiation dose and fractionation as well as scheduling for therapeutic application, it is essential to gain detailed insight into the molecular basis of genotoxic and immune modulatory effects of radiotherapy. The following paragraph will summarize current knowledge on effects of radiotherapy that result from direct damage on tumor cells  with subsequent effects on the inflammatory response against tumors. Moreover, local and systemic immune responses can also be modulated by radiation-induced changes in different cell populations of the tumor microenvironment . Direct The central dogma of traditional radiobiology states that effects of radiation on tumor cells are primarily due to the generation of double strand breaks that lead to the induction of different forms of cell death including apoptosis, necrosis, autophagy, or mitotic catastrophe . Apart fWithin the process of immune evasion, tumor cells acquire traits that mask the tumor from immune surveillance and destruction. The immune escape stage is characterized by up-regulation of inhibitory ligands and cytokines, reduced MHCI expression, and increased number of suppressive cell types such as Tregs . RadiothRadiation-induced DNA damage that causes leakage of DNA into the cytosol is known to be sensed by the stimulator of interferon gens (STING) leading to the activation of innate and adaptive immune responses . The STIDetermining the optimal scheduling for radio-immunotherapy is a major challenge for the field and requires carefully designed prospective clinical studies together with comprehensive studies in animal models to test effects of different treatment regimens , 149. AsAnother important factor that determines synergy of radio-immunotherapy is the cellular composition of the tumor microenvironment . As discTaken together, radiation dose and fractionation have profound effects on the induction of genotoxic and immunogenic effects. Systematic interrogation of the dose dependency of immune responses directed against different cancer types is needed to determine optimal regimens to increase the immunogenicity of tumors and boost the immune system for effective anti-tumor responses that synergize with immunotherapy.To date, clinical and pre-clinical data suggest that combining radiotherapy with immunotherapy show higher efficacy compared to mono-therapies. These results represent promising first steps in the quest for improved treatment options for brain cancer patients. However, it is also evident that many hurdles exist that prevent higher response rates and more sustainable anti-tumor reactions. While individual patients show prominent cerebral responses, significant effects on overall survival are rarely reported. This indicates that the pressure of the CNS to establish an immunosuppressive environment is dominant over the attempt to unleash the immune system by immune checkpoint blockade. Based on our current mechanistic understanding of the cellular and molecular drivers of immune-suppression in the steady-state CNS and in the context of cerebral cancers, different approaches appear as viable strategies to overcome the highly immune-suppressive environment in the CNS. Based on the results that TAM-BMDM rather than TAM-MG are implicated in tumor-promotion and immune-suppression, selective depletion or blockade of TAM-BMDM recruitment could lead to more effective T cell activation and execution of anti-tumor effector functions. In addition, systems that would allow more efficient recruitment of T cells into CNS tumors could significantly boost cytotoxic T cell responses directed against tumor neo-antigens. A recent study by Samaha et al. reported the engineering of T cells with an Activated Leukocyte Cell Adhesion Molecule (ALCAM) homing system (HS) . In thisA close link between radiotherapy and the immune system has been proposed already 100 years ago by Russ and Murphy . Murphy'The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.