Cancer being a multi-factorial disease, a multi-target approach is needed to treat it with minimal side-effects. Therefore, combined use of a proven herbal formula with chemo-therapy could be the better therapeutic. It may maintain homeostasis by synergistically targeting multiple signaling pathways involved in tumorigenesis, thus circumventing recurrence, resistance, and immunosuppression. Here we aim to determine the effectiveness and safety of an FDA-approved herbal formula, SR033 in combination with 5-fluorouracil (5FU) and paclitaxel (PTX). We report chemo-sensitization and chemo-synergy in HeLa and MCF-7 cell lines, immunomodulation of COX-2, PD-L1, VEGF and TGFβ and overall survival in-vitro and in-vivo via oral and topical delivery of SR033. In-vitro, SR033/5FU significantly reverses 5FU and PTX-resistance, lower COX-2, and PD-L1, resulting in TGFβ/ VEGF axis modulation. Furthermore, the study suggests that due to anti-oxidative potential of SR033, oral administration exerts chemo-preventive activity and restores cellular compartment in solid tumor and ascites-bearing mice models. Furthermore, the topical application, SR033L with low-dose 5FU increases survival rate, reduces tumor growth, and completely restores local and peripheral neutrophil-lymphocyte ratio in solid tumor mice model. The study indicates that SR033 could be a strong candidate in combination with low-dose 5FU and PTX for a holistic approach to cancer management.

Although many attempts have been made to improve the efficacy of radiotherapy to treat cancer, radiation resistance is still an obstacle in lung cancer treatment. Oridonin is a natural compound with promising antitumor efficacy that can trigger cancer cell death; however, its direct cellular targets, efficacy as a radiosensitizer, and underlying mechanisms of activity remain unclear. Herein, we report that oridonin exhibits additive cytotoxic and antitumor activity with radiation using H460 non-small cell lung cancer cell lines. We assessed the radiosensitizing effect of oridonin by MTT, clonogenic, reactive oxygen species (ROS) production, DNA damage, and apoptosis assays. In vitro, oridonin enhanced the radiation-induced inhibition of cell growth and clonogenic survival. Oridonin also facilitated radiation-induced ROS production and DNA damage and enhanced apoptotic cell death. In vivo, the combination of oridonin and radiation effectively inhibited H460 xenograft tumor growth, with higher caspase-3 activation and H2A histone family member X (H2AX) phosphorylation compared with that of radiation alone. Our findings suggest that oridonin possesses a novel mechanism to enhance radiation therapeutic responses by increasing DNA damage and apoptosis. In conclusion, oridonin may be a novel small molecule to improve radiotherapy in non-small cell lung cancer.

Groundwater contamination by nitrate and organic chemicals (e.g. 1,4-dioxane) is a growing worldwide concern. This work presents a new approach for simultaneously treating nitrate and 1,4-dioxane, which is based on UV sensitization of nitrate and sulfite, and the production of reactive species. Specifically, water contaminated with nitrate and 1,4-dioxane is irradiated by a UV source (< 250 nm) at relatively high doses, to sensitize in-situ nitrate and generate HO•. This leads to the oxidation of 1,4-dioxane (and other organics), and the (undesired) production of nitrite as an intermediate. Subsequently, sulfite is added at an optimized time-point, and its UV sensitization produces hydrated electrons which reacts and reduces nitrite. Our results confirmed the effectivity of the proposed treatment: UV irradiation of nitrate (at > 5 mg N/L) efficiently degraded 1,4-dioxane, while producing nitrite at levels higher than 1 mg N/L (its MCL in drinking water). Adding sulfite to the process after 10 minutes of irradiation reduced the concentration of nitrite, without affecting the degradation rate of 1,4-dioxane. The treated water contained elevated levels of sulfate; albeit at much lower concentration than its MCL. Treating water contaminated with nitrate and organic chemicals (often detected concomitantly) typically requires several (expensive) treatment processes. The proposed approach may present a cost-effective alternative, employing a single system for the treatment of nitrate and organic contaminants

This review explores the application of the conservative management model for pain to sports-related concussions (SRCs), framing concussions as a distinct form of pain syndrome with a pathophysiological foundation in central sensitization. Drawing parallels with proven pain management models, we underscore the significance of a proactive approach to concussion management. Recognizing concussions as a pain syndrome allows for the tailoring of interventions in alignment with conservative principles. This review first covers the epidemiology and controversies surrounding prolonged concussion recovery and persistent post-concussion symptoms (PPCS). Next, the pathophysiology of concussions is presented within the central sensitization framework, emphasizing the need for early intervention to mitigate the neuroplastic changes that lead to heightened pain sensitivity. Five components of the central sensitization process specific to concussion injuries are highlighted as targets for conservative interventions in the acute period: peripheral sensitization, cerebral metabolic dysfunction, neuroinflammation, glymphatic system dysfunction, and pain catastrophizing. These proactive interventions are emphasized as pivotal in accelerating concussion recovery and reducing the risk of prolonged symptoms and PPCS, in line with the philosophy of conservative management.

Pancreatic Ductal Adenocarcinoma (PDAC) is the most frequent infiltrating type of pancreatic cancer. The poor prognosis is due to the absence of specific biomarkers, aggressiveness and treatment resistance. PDAC is a deadly malignancy bearing distinct genetic alterations, the most common being those that cause cancer-causing versions of the KRAS gene. Cannabigerol (CBG) is a non-psychomimetic cannabinoid with anti-inflammatory property. Regarding CBG anticancer ef-fect, up to now there are only few evidence in human cancers. We investigated CBG effects on PDAC cell lines, PANC-1 and MIAPaCa-2. It was investigated CBG activity on cell viability, cell death and its effect of EGFR-RAS-associated signalling. Moreover, the potential synergistic effect of CBG in combination with gemcitabine (GEM) and paclitaxel (PTX) was investigated. MTT was applied to investigate CBG effect on PDAC cell lines viability. Annexin-V and Acridine Orange staining followed by cytofluorimetric analysis and Western blot were used to evaluate CBG effect on cell death. Modulation of EGFR-RAS-associated pathways was determined by Western Blot analysis and Milliplex multiplex assay. Moreover, by MTT data and Synergy finder software analysis the effect of the combination of CBG and chemotherapeutic drugs, was determined.

In this paper we study a bilinear optimal control problem related to a 2D parabolic-elliptic chemo-repulsion system consider a nonlinear chemical signal production term. We prove the existence of global optimal solutions with bilinear control, and applying a result on the existence of Lagrange multipliers in Banach spaces, we derive an optimality system for a local optimal solution.

Repeated cocaine produces an enhanced locomotor response (sensitization) paralleled by biological adaptations in the brain. Previous studies demonstrated region-specific responsiv-ity of adenosine monophosphate-activated protein kinase (AMPK) to repeated cocaine. AMPK maintains cellular energy homeostasis at the organismal and cellular level. Here we first quanti-fied changes in phosphorylated (active) and total AMPK in the cytosol and synaptosome of the medial prefrontal cortex, nucleus accumbens, and dorsal striatum following acute or sensitizing cocaine injections. Rats were given cocaine (15 mg/kg, IP) or saline for six days with a challenge injection on day seven resulting in four groups: saline-saline, saline-cocaine, cocaine-saline, and cocaine-cocaine. Brain region and cellular compartment selective changes in AMPK and pAMPK were found with some differences associated with acute withdrawal versus ongoing cocaine treatment. Other rats were pretreated with the indirect AMPK activator metformin. Metformin potentiated the locomotor activating effects of acute cocaine but blocked the development of sensi-tization. Sex differences largely obscured protein level treatment group effects, although pAMPK in the NAc shell cytosol was surprisingly reduced by metformin in rats receiving repeated co-caine. These data inform our understanding of AMPK activation dynamics in subcellular com-partments and provide additional support for repurposing metformin for cocaine use disorder.

We demonstrate high quality (intrinsic Q factor ~2.8×106) racetrack microresonators fabricated on lithium niobate (LN) thin film with a free spectral range (FSR) of ~86.38 pm. By integrating microelectrodes alongside the two straight arms of the racetrack resonator, the resonance wavelength around the 1550 nm can be red shifted by 92 pm when the electric voltage is raised from -100 V to 100 V. The microresonators of the tuning range spanning over a full FSR is fabricated using photolithography assisted chemo-mechanical etching (photolithography assisted chemo-mechanical etching, PLACE).

Asthma is a heterogeneous and very complex group of diseases, which includes different clinical phenotypes depending on symptoms, progression, exacerbation pattern or response to treatment among other characteristics. The allergic phenotype is the most frequent, especially in pediatric asthma. It is characterized by sensitization (production of specific IgE) to allergens, and frequent comorbidity with rhinitis and atopic dermatitis. An allergen is a substance that triggers the production of specific IgE antibodies in susceptible individuals, who present symptoms that will depend on the type and intensity of the allergenic load and the tissue where the interaction occurs. Airborne allergens cause their effects in the respiratory tract and eyes, and can be indoor or outdoor, perennial or seasonal. Although allergens such as mites, pollens or animal dander are generally considered as a single particle, it is important to note that they contain different molecules which could trigger distinct specific IgE molecules on different patients.The key points that a physician who treats asthma should be aware of are:

Gastric cancer, also known as stomach cancer, is a cancer which develops from the lining of the stomach. Accumulated evidences and epidemiological studies have been indicated that natural products play an important role in gastric cancer prevention and treatment, although its mechanism of action did not elucidate yet. Particularly, experimental studies have been showed that natural products displayed a protective effect against gastric cancer via numerous molecular mechanisms such as suppression of cell metastasis, anti-angiogenesis, inhibition of cell proliferation, induction of apoptosis, and modulation of autophagy. Although chemotherapy remains the standard treatment for advanced gastric cancer along with surgery, radiation therapy, hormone therapy and immunotherapy, but its adverse side effects including neutropenia, stomatitis, mucositis, diarrhea, nausea, and emesis are well documented. Additionally, intake of naturally occurring phytochemicals could increase the efficacy of gastric chemotherapy and chemotherapeutics resistance. However, natural product structural stability and powerful bioactivity are important to develop novel treatments for gastric cancer that may minimize such adverse effects. Therefore, the purpose of this review is to summarize the potential therapeutic effects of natural products on prevention and treatment of gastric cancer with intensive molecular mechanisms of action, bioavailability, and safety efficacy.

The SBA-15 loaded with methylene blue was successfully prepared by sample adsorption of methylene blue in SBA-15 and is characterized by an XRD, SEM, FTIR, and BET. The photocatalytic activity for methyl orange (MO) degradation was investigated under visible light irradiation under LEDs. Experimental results demonstrate that the SBA-15-MB exhibited higher photocatalytic activity than SBA-15 under visible light irradiation. The degradation efficiency of MO (50 ppm) by SBA-15-MB could reach 80% within 180 min under 25W LED visible light. The photocatalytic activity of SBA-15 could be attributed to the excitation of methylene blue by visible light, the transfer of electrons from methylene blue to SBA-15, and the production of radicals at the surface of SBA-15.

Oxytocin (OXT), a pro-social peptide, is increasingly recognized as a potential protective substance against drug addiction. In the context of ethanol, previous researches have shown OXT properties to reduce self-administration, alleviate motor impairment in rodents, and reduce craving in humans. However, its role in behavioral sensitization, a neuroadaptive response resulting from repeated drug exposure linked to increased drug incentive, remains unexplored. OXT is also associated with modulating the Hypothalamic-Pituitary-Adrenal (HPA) axis, with corticosterone well-known as a significant factor in behavioral sensitization development. This study aimed to investigate the effects of Carbetocin (CBT), an analogue of OXT, on the expression of behavioral sensitization to ethanol and concurrent alterations in plasma corticosterone levels in male and female Swiss mice. We also aimed to confirm previous studies on OXT impact on ethanol consumption in male mice, but with a focus on CBT, using the two-bottle choice model and drinking in the dark (DID) methodology. For the sensitization study, mice received either ethanol (1.8 g/kg, ip) or saline treatments daily for 15 consecutive days, followed by treatment with carbetocin (0.64 mg/kg, ip) or a vehicle for 6 days. Subsequently, on day 22, all animals underwent an ethanol challenge to assess the expression of behavioral sensitization. Plasma corticosterone levels were measured on days 21 and 22. CBT effectively prevented the expression of ethanol-induced behavioral sensitization in both male and female subjects, with no alterations detected in corticosterone levels. In the ethanol consumption study, following an initial phase of ethanol acquisition, mice underwent a 6-day treatment with CBT i.p or saline before being reexposed to ethanol. We also found a reduction in ethanol consumption due to CBT treatment. In conclusion, carbetocin emerges as a promising and effective intervention in mitigating ethanol-induced behavioral sensitization and reducing ethanol intake, highlighting its potential significance in alcohol addiction treatment.

Windup, a progressive increase in spinal response to repetitive stimulations of nociceptive peripheral fibres, is a useful model to study central sensitization to pain. Windup is expressed by neurons in of both dorsal and ventral horn of the spinal cord. In juvenile rats, it has been demonstrated both in vivo and in vitro that windup depends on calcium-dependent intrinsic properties and their modulation by synaptic components. However, the involvement of these two components in the adult remain controversial. In the present study, by means of electromyographic and extracellular recordings, we show that windup in adult, in vivo, depends on a synaptic balance between excitatory NMDA receptors and inhibitory glycinergic receptors. We also demonstrate the involvement of L-type calcium channels in both the dorsal and ventral horn of the spinal cord. These results indicate that windup in adults is similar to juveniles rats and that windup properties are the same regardless spinal network, i.e. sensory or motor.

This paper investigates the evolution of microstructures and precipitations of an ultra-low iron alloy 625 subjected to long term aging treatment by scanning electron microscope (SEM) and X-ray diffraction(XRD). Use ASTM G28A acid Fe3(SO4)2 erosion to represent intergranular corrosion weightlessness and corrosive morphology. The result shows that alloy at 750C by aging treatment for 40h, precipitated γ'' phase in the grain boundary. In high density area of γ'' phase, occurs γ'' phase to δ phase degeneration transformation by aging treatment for 200h and the needle-like δ phase becomes more with time prolonged. And γ'' phase degenerated to δ phase completely until treated for 1000h. The sample which has aging treatment tends to have intergranular corrosion and mainly because alloy element spreading leads to dilution area and grain boundary precipitated phase, plus interlaced δ phase’s dissolving, which makes sample grain particle fall off and this results in apparent weightlessness. The weightlessness rate(WLR) is related with precipitated volume score. With aging sensitization time change, can be described by Johnson-Mehl-Avrami equation, i.e.: $WLR=44.32\left[1-\text{exp}\left(-\frac{t}{10.99}\right)\right]+44.62\left[1-\text{exp}\left(-\frac{t}{327.8}\right)\right]+1.267\left(mm/a\right)$

We demonstrate fabrication of single-mode optical waveguides on lithium niobate on insulator (LNOI) by optical patterning combined with chemo-mechanical polishing. The fabricated LNOI waveguides have a nearly symmetric mode profile of a mode field size of ~2.5 µm (full-width at half maximum). We develop a high-precision measurement approach by which the single mode waveguides are characterized to have a propagation loss of ~0.042 dB/cm.

We report fabrication of a multifunctional photonic integrated chip on lithium niobate on insulate (LNOI), which is achieved by femtosecond laser assisted chemo-mechanical polish. We demonstrate a high extinction ratio beam splitter, a 1 × 6 optical switch, and a balanced 3 × 3 interferometer on the fabricated chip by reconfiguring the microelectrode array integrated with the multifunctional photonic circuit.

Due to similarities in genetics, cellular response, and behavior, Drosophila is used as a model organism in addiction research. A well described behavioral response examined in flies is the induced increase in locomotor activity after a single dose of volatilized cocaine (vCOC) and volatilized methamphetamine (vMETH) known as sensitivity, and the escalation of the locomotor response after the repeated dose, known as the locomotor sensitization. However, knowledge about how vCOC and vMETH affect different neurotransmitter systems over time is scarce. We used LC-MS/MS to systematically examine changes in the concentration of neurotransmitters, metabolites and non-metabolized COC and METH in the whole head homogenates of male flies one to seven hours after single and double vCOC or vMETH administrations. vMETH leads to complex changes in the levels of examined substances over time, while vCOC strongly and briefly increases concentrations of dopamine, tyramine and octopamine followed by a delayed degradation into N-acetyl dopamine and N-acetyl tyramine. The first exposure to psychostimulants leads to significant and dynamic changes in the concentrations relative to the second administration when they are more stable over several hours. Further investigations are needed to understand neurochemical and molecular changes post-psychostimulant administration.

Alteration in heparan sulfate (HS) biosynthesis has been described to impact a range of pivotal processes involved in cancer progression. HS 3-O-sulfotransferase 3B1 (HS3ST3B1) catalyzes the reaction of 3-O-sulfation within HS chains. Over the past few years, a growing number of studies has reported a tumor-promoting effect of this HS-modifying enzyme in various cancers. Consistent with these studies, we previously reported that HS3ST3B1 overexpression increased survival and resistance to apoptosis in MDA-MB-231 breast cancer (BrCa) cells. In the present study, we further investigated the biological and clinical significance of HS3ST3B1 expression in BrCa. Interrogation of public databases revealed that high expression levels of HS3STB1 are associated with invasive and mesenchymal-like phenotype in BrCa cells and predict poor clinical outcome in BrCA patients with chemotherapy. In vitro, HS3ST3B1 overexpression increased the invasive properties of MDA-MB-231 cells and enhanced chemo-resistance to conventional anticancer drugs. Mechanistically, we found that the advantage given by HS3ST3B1 was linked to the expression and activation of PDGF-Rβ. Silencing the expression of this receptor reversed the effects driven by HS3ST3B1 overexpression. Altogether, our results suggest that HS3ST3B1 may play an important role in the progression of aggressive BrCa and offer a potentially druggable target for therapeutic application.

De-escalation is currently taking place both in surgical and systemic treatment of breast cancer. The introduction of trastuzumab, the first monoclonal antibody against the HER2 receptor over 20 years ago was a milestone in the treatment of HER2 positive breast cancer and marked the beginning of a new era in targeted tumor therapy. In the sense of de-escalation, omitting non-targeted cytotoxic chemotherapy altogether is often hailed as the ultimate goal of oncological research. Especially in case of small, node-negative, HER2 positive early breast cancer, it remains a challenge for clinicians to establish the safest and most efficient treatment plan while considering the significant potential for toxic side effects associated with chemotherapy and HER2 targeted therapy, and the generally excellent prognosis. In this context, several ongoing studies are currently assessing chemotherapy-free regimens as part of strategies aimed at de-escalating therapy in the field of HER2 positive early breast cancer. Despite promising early results from these studies, combination of anti-HER2 treatment with chemotherapy backbone remains standard of care.

We demonstrate hybrid integration of a lithium niobate microring resonator with a silicon nitride waveguide in the vertical configuration to achieve efficient light coupling. The microring resonator is fabricated on a lithium niobate on insulator (LNOI) substrate using photolithography assisted chemo-mechanical etching (PLACE). A fused silica cladding layer is deposited on the LNOI ring resonator. The silicon nitride waveguide is further produced on the fused silica cladding layer by first fabricating a trench in the fused silica using focused ion beam (FIB) etching for facilitating the evanescent coupling, followed by formation of the silicon nitride waveguide on the bottom of the trench. The FIB etching ensures the required high positioning accuracy between the waveguide and the ring resonator. We achieve Q-factors as high as 1.4*10^7 with the vertically integrated device.

We report fabrication of crystalline microresonators of high quality (Q) factors with a controllable wedge angle on lithium niobate on insulator (LNOI). Our technique relies on femtosecond laser assisted chemo-mechanical polish which allows us to achieve ultrahigh surface smoothness as critically demanded by high Q microresonator applications. We show that by refining the polish parameters, Q factors as high as 4.7 × 10⁷ can be obtained and the wedge angle of the LNOI can be continuously tuned from 9° to 51°.

We develop a technique for realizing lithium niobate on insulator (LNOI) waveguides of a multi-centimeter-length with a propagation loss as low as 0.027 dB/cm. Our technique relies on patterning a chromium (Cr) thin film coated on the top surface of LNOI into a hard mask with a femtosecond laser followed by the chemo-mechanical polishing for structuring the LNOI into the waveguides. The surface roughness on the waveguides is determined to be 0.452 nm with an atomic force microscope (AFM). The approach is compatible with other surface patterning technologies such as optical and electron beam lithographies or laser direct writing, enabling high-throughput manufacturing of large-scale LNOI-based photonic integrated circuits.

Phantom Limb Pain (PLP) is a challenging condition affecting a significant proportion of amputees. In this article we describe the case of a 54-year-old Paralympic athlete with Phantom Limb Syndrome following right leg amputation and widespread sports-related enthesitic pain, who underwent a Whole Body Cryostimulation (WBC) cycle, an emerging treatment known for its rapid pain-relieving and anti-inflammatory effects. Assessments were conducted before and after a 10-session WBC cycle, including pain and quality of life assessment, and use of medications. A substantial reduction in enthesitic pain, PLP intensity, paresthesia, tingling related to atmospheric events and an improved function and quality of life were reported after the WBC cycle and lasted for two weeks. One month after WBC, the enthesitic pain following sports activity and PLP gradually returned but with lesser intensity. Similarly, the stump's sensitivity to atmospheric changes returned but with lower frequency. Pain at night remained lower than before WBC with significantly improved quality of sleep. This case study suggests that WBC could be a valuable adjuvant treatment for alleviating PLP. Controlled studies are warranted to validate the findings of this case-report and elucidate the mechanisms underlying the positive effects of WBC in this condition.

Music perception in foetuses has been explored under different theoretical paradigms such as habituation, categorical perception, sound preferences and recall. This study investigated the temporal dimension of music perception through the habituation and sensitization paradigm. Foetuses of 41 pregnant women, mean gestational age of 34.7 weeks (±2.4), were observed during ultrasound exams. Foetuses’ reaction to two different tempos (Allegro vs Adagio) and sources (internal vs external) of music stimuli was registered by heart rate variability (HR) and motor response according to the Assessment of Preterm Infants Behaviour scale (APIB) by its factors of movement (MOV) and organization (ORG). A folkloric lullaby, sung and played live with a stringed instrument by a musician, was presented in three stages that were compared to baseline: 1) slow tempo (Adagio), 2) fast tempo (Allegro); and 3) now sung by mother at slow tempo (Adagio). Exploratory analyses showed that all factors increased from baseline to first stage. HR and ORG varied significantly among stages, with HR being the strongest factor. MOV merely detected change from baseline to first stage. ORG decreased for Allegro but increased for maternal Adagio, while HR decreased to near baseline values. ANOVA-repeated measures with gestational age as covariate showed that all measures were sensitive to first music presentation (Adagio), although only HR and ORG differed among stages. Considering estimated marginal means, adjusted for gestational age, HR presented a sensitization pattern throughout stages, but ORG kept habituating to external source and increased to maternal Adagio, suggesting foetal discrimination by sound source. We conclude that foetuses showed different behavioural and physiological responses to external versus internal sound source and musical tempo. The combined use of a behavioural scale (APIB) and HR in foetuses proved to be a valid multidimensional instrument.

In contrast to Th1 immune responses against pathogenic viruses and bacteria, the incipient events that generate Th2 responses remain less understood. Part of the difficulty in identifying universal operating principles stems from the diversity of entities against which cellular and molecular Th2 responses are produced. Indeed, such responses are launched towards harmful macroscopic parasites and noxious substances such as venoms but also against largely innocuous allergens. This suggests that the canonical understanding about sensing and recognition applied to Th1 responses may not be translatable to Th2 responses. This review will discuss processes and signals known to occur in Th2 responses, particularly in the context of food allergy. We propose that perturbations of homeostasis at barrier sites induced by external or internal subverters that either activate the immune system or lower its threshold activation are the major requirement for allergic sensitization. Innate signals produced in the tissue under these conditions equip dendritic cells with a program that shapes an adaptive Th2 response.

Men with non-small cell lung cancer (NSCLC) have a more favorable response to immune-checkpoint inhibitor (ICI) monotherapy, while women especially benefit from ICI-chemotherapy (CHT) combinations. To elucidate such sex differences in clinical practice, we retrospectively analyzed two cohorts treated with either ICI monotherapy (n=228) or ICI-CHT combination treatment (n=80) for advanced NSCLC. Kaplan-Meier analyses were used to calculate progression-free (PFS) and overall survival (OS), influencing variables were evaluated using Cox-regression analyses. No significant sex differences for PFS/OS could be detected in either cohort. Men receiving ICI monotherapy had a statistically significant independent impact on PFS by Eastern Cooperative Oncology Group performance status (ECOG) ≥2 (hazard ratio (HR) 1.90, 95% confidence interval (CI): 1.10-3.29, p=0.021), higher C-reactive protein (CRP; HR 1.06, 95%CI: 1.00-1.11, p=0.037) and negative programmed death-ligand 1 (PD-L1) status (HR 2.04, 95%CI: 1.32-3.15, p=0.001), and on OS by CRP (HR 1.09, 95%CI: 1.03-1.14, p=0.002). In men on ICI-CHT combinations, multivariate analyses (MVA) revealed squamous histology (HR 4.00, 95%CI: 1.41-11.2, p=0.009) significant for PFS; ECOG≥2 (HR 5.58, 95%CI: 1.88-16.5, p=0.002) and CRP (HR 1.19, 95%CI: 1.06-1.32, p=0.002) for OS. Among women undergoing ICI monotherapy, no variable proved significant for PFS, ECOG≥2 had a significant interaction with OS (HR 1.90, 95%CI 1.04-3.46, p=0.037). Women treated with ICI-CHT had significant MVA findings for CRP with both PFS (HR 1.09, 95%CI: 1.02-1.16, p=0.007) and OS (HR 1.11, 95%CI: 1.03-1.19, p=0.004). Although men and women responded similarly to both ICI mono- and ICI-CHT treatment, predictors of response differed by sex.

Although work events can be regarded as pivotal elements of organizational life, only a few studies have examined how positive and negative events relate to and combine to affect work engagement over time. Theory suggests that to better understand how current events affect work engagement (WE), we have to account for recent events that have preceded these current events. We present competing theoretical views on how recent and current work events may affect employees (e.g., getting used to a high frequency of negative events or becoming more sensitive to negative events). Although the occurrence of events implies discrete changes in the experience of work, prior research has not considered whether work events actually accumulate to sustained mid-term changes in WE. To address these gaps in the literature, we conducted a week-level longitudinal study across a period of 15 consecutive weeks among 135 employees, which yielded 849 weekly observations. While positive events were associated with higher levels of WE within the same week, negative events were not. Our results support neither satiation nor sensitization processes. However, high frequencies of negative events in the preceding week amplified the beneficial effects of positive events on WE in the current week. Growth curve analyses show that the benefits of positive events accumulate to sustain high levels of WE. WE dissipates in the absence of continuous experience of positive events. Our study adds a temporal component and informs research that has taken a feature-oriented perspective on the dynamic interplay of job demands and resources.

A major advance of drug discovery and targeted therapy directed to cancer cells may be achieved by exploitation and immunomodulation of their unique biological property. This re-view summarizes our efforts to develop novel chemo-thermo-immuno-therapy (CTI therapy) by conjugating a melanogenesis substrate, N-propionyl cysteaminylphenol (NPrCAP: amine analog of tyrosine), with magnetite nanoparticles (MNP). In our approach, NPrCAP provides a unique drug delivery system (DDS) because of its selective incorporation into melanoma cells. It also functions as a melanoma-targeted therapeutic drug because of its production of highly reactive free radicals (melanoma-targeted chemotherapy). Moreover, utilization of MNP is a platform to develop thermo-immunotherapy because of heat shock protein (HSP) generation upon exposure to an alternating magnetic field (AMF). The feasibility of our approach was successfully shown in experimental in vivo and in vitro mouse melanoma models and in preliminary clinical trials to a limited number of advanced melanoma patients.

The ability to predict the skin sensitization potential of small organic molecules is of high importance to the development and safe application of cosmetics, drugs and pesticides. One of the most widely accepted methods for predicting this hazard is the rodent local lymph node assay (LLNA). The goal of this work was to develop in silico models for the prediction of the skin sensitization potential of small molecules that go beyond the state of the art, with larger LLNA data sets and, most importantly, a robust and intuitive definition of the applicability domain, paired with additional indicators of the reliability of predictions. We explored a large variety of molecular descriptors and fingerprints in combination with random forest and support vector machine classifiers. The most suitable models were tested on holdout data, on which they yielded competitive performance (Matthews correlation coefficients up to 0.52; accuracies up to 0.76; areas under the receiver operating characteristic curves up to 0.83). The most favorable models are available via a public web service at https://nerdd.zbh.uni-hamburg.de/skinDoctor/ that, in addition to predictions, provides assessments of the applicability domain and indicators of the reliability of the individual predictions.