Unusual non-infectious cause of meningitis.

Meningitis, though commonly caused by various infectious agents, may also have non-infectious aetiologies. The clinical presentation, however may be identical to infectious meningitis. We present a case of a female in her 50s who presented with fever, headache, vomiting and neck rigidity. She had features of inflammatory polyarthritis, cold sensitivity, puffy digits, alopecia and easy fatigability. No evidence of infection was found, and serological features consistent with mixed connective tissue disease (MCTD) were revealed, which led to the diagnosis of MCTD-related aseptic meningitis.

meso-Methyl BODIPY Photocages: Mechanisms, Photochemical Properties, and Applications.

meso-methyl BODIPY photocages have recently emerged as an exciting new class of photoremovable protecting groups (PPGs) that release leaving groups upon absorption of visible to near-infrared light. In this Perspective, we summarize the development of these PPGs and highlight their critical photochemical properties and applications. We discuss the absorption properties of the BODIPY PPGs, structure-photoreactivity studies, insights into the photoreaction mechanism, the scope of functional groups that can be caged, the chemical synthesis of these structures, and how substituents can alter the water solubility of the PPG and direct the PPG into specific subcellular compartments. Applications that exploit the unique optical and photochemical properties of BODIPY PPGs are also discussed, from wavelength-selective photoactivation to biological studies to photoresponsive organic materials and photomedicine.

Engineering donor lymphocytes with Fas ligand protein effectively prevents acute graft-versus-host disease.

Alloreactive T-effector cells (Teffs) are the major culprit of acute graft-versus-host disease (aGVHD) associated with hematopoietic stem cell transplantation. Ex vivo nonspecific depletion of T cells from the donor graft impedes stem cell engraftment and posttransplant immune reconstitution. Teffs upregulate Fas after activation and undergo Fas ligand (FasL)-mediated restimulation-induced cell death (RICD), an important mechanism of immune homeostasis. We targeted RICD as a means to eliminate host-reactive Teffs in vivo for the prevention of aGVHD. A novel form of FasL protein chimeric with streptavidin (SA-FasL) was transiently displayed on the surface of biotinylated lymphocytes, taking advantage of the high-affinity interaction between biotin and streptavidin. SA-FasL-engineered mouse and human T cells underwent apoptosis after activation in response to alloantigens in vitro and in vivo. SA-FasL on splenocytes was effective in preventing aGVHD in >70% of lethally irradiated haploidentical mouse recipients after cotransplantation with bone marrow cells, whereas all controls that underwent transplantation with nonengineered splenocytes developed aGVHD. Prevention of aGVHD was associated with an increased ratio of CD4+CD25+FoxP3+ T regulatory (Tregs) to Teffs and significantly reduced transcripts for proinflammatory cytokines in the lymphoid organs and target tissues. Depletion of Tregs from the donor graft abrogated the protection conferred by SA-FasL. This approach was also effective in a xenogeneic aGVHD setting where SA-FasL-engineered human PBMCs were transplanted into NSG mice. Direct display of SA-FasL protein on donor cells as an effective means of eliminating alloreactive Teffs in the host represents a practical approach with significant translation potential for the prevention of aGVHD.

Photocaged DNA-Binding Photosensitizer Enables Photocontrol of Nuclear Entry for Dual-Targeted Photodynamic Therapy.

Photodynamic therapy (PDT) is a clinically approved cancer treatment that requires a photosensitizer (PS), light, and molecular oxygen─a combination which produces reactive oxygen species (ROS) that can induce cancer cell death. To enhance the efficacy of PDT, dual-targeted strategies have been explored where two photosensitizers are administered and localize to different subcellular organelles. To date, a single small-molecule conjugate for dual-targeted PDT with light-controlled nuclear localization has not been achieved. We designed a probe composed of a DNA-binding PS (Br-DAPI) and a photosensitizing photocage (WinterGreen). Illumination with 480 nm light removes WinterGreen from the conjugate and produces singlet oxygen mainly in the cytosol, while Br-DAPI localizes to nuclei, binds DNA, and produces ROS using one- or two-photon illumination. We observe synergistic photocytotoxicity in MCF7 breast cancer cells, and a reduction in size of three-dimensional (3D) tumor spheroids, demonstrating that nuclear/cytosolic photosensitization using a single agent can enhance PDT efficacy.

The Innate Immune System in Cardiovascular Diseases and Its Role in Doxorubicin-Induced Cardiotoxicity.

Innate immune cells are the early responders to infection and tissue damage. They play a critical role in the initiation and resolution of inflammation in response to insult as well as tissue repair. Following ischemic or non-ischemic cardiac injury, a strong inflammatory response plays a critical role in the removal of cell debris and tissue remodeling. However, persistent inflammation could be detrimental to the heart. Studies suggest that cardiac inflammation and tissue repair needs to be tightly regulated such that the timely resolution of the inflammation may prevent adverse cardiac damage. This involves the recognition of damage; activation and release of soluble mediators such as cytokines, chemokines, and proteases; and immune cells such as monocytes, macrophages, and neutrophils. This is important in the context of doxorubicin-induced cardiotoxicity as well. Doxorubicin (Dox) is an effective chemotherapy against multiple cancers but at the cost of cardiotoxicity. The innate immune system has emerged as a contributor to exacerbate the disease. In this review, we discuss the current understanding of the role of innate immunity in the pathogenesis of cardiovascular disease and dox-induced cardiotoxicity and provide potential therapeutic targets to alleviate the damage.

Efficiency of Functional Group Caging with Second-Generation Green- and Red-Light-Labile BODIPY Photoremovable Protecting Groups.

BODIPY-based photocages release substrates by excitation with wavelengths in the visible to near-IR regions. The recent development of more efficient BODIPY photocages spurred us to evaluate the scope and efficiency of these second-generation boron-methylated green-light and red-light-absorbing BODIPY photocages. Here, we show that these more photosensitive photocages release amine, alcohol, phenol, phosphate, halides, and carboxylic acid derivatives with much higher quantum yields than first-generation BODIPY photocages and excellent chemical yields. Chemical yields are near-quantitative for the release of all functional groups except the photorelease of amines, which react with concomitantly photogenerated singlet oxygen. In these cases, high chemical yields for photoreleased amines are restored by irradiation under an inert atmosphere. The photorelease quantum yield has a weak relationship with the leaving group pKa of the green-absorbing BODIPY photocages but little relationship with the red-absorbing derivatives, suggesting that factors other than leaving group quality impact the quantum yield. For the photorelease of alcohols, in all cases a carbonate linker (that loses CO2 upon photorelease) significantly increases both the quantum yield and the chemical yield compared to those for direct photorelease via the ether.

Modified norcyanines enable ratiometric pH imaging beyond 1000 nm.

Activatable fluorophores with emission beyond 1000 nm have the potential to enable high contrast imaging in complex in vivo settings. However, there are few scaffolds that can be applied to this challenge. Here we detail the synthesis and evaluation of benzo[c,d]indole-substituted norcyanines that enable pH responsive fluorescence imaging in the long wavelength (>1150 nm) range. A key component of our molecular design is the installation of a hydrophilic substituted quaternary amine in the central dihydropyridine ring system. A compound with a C4'-phenyl substituent, but not the C4'-protio homologue, exhibits absorbance maxima of 740 nm and 1130 nm in basic and acidic media, respectively, with evidence of J-aggregate-like properties. These two distinct absorbances enabled ratiometric imaging of probe internalization in a tumor model. Overall, these studies provide a new class of activatable long-wavelength responsive fluorophores with promising photophysical properties.

Doxorubicin-induced cardiotoxicity is mediated by neutrophils through release of neutrophil elastase.

The mechanisms by which Doxorubicin (Dox) causes acute and late cardiotoxicity are not completely understood. One understudied area is the innate immune response, and in particular the role of neutrophils in Dox-induced cardiotoxicity. Here, using echocardiography, flow cytometry and immunofluorescence staining, we demonstrated increased infiltration of neutrophils that correlated with decreased heart function, disruption of vascular structures and increased collagen deposition in the heart after Dox treatment. Depleting neutrophils protected the heart from Dox-induced cardiotoxicity and changes in vascular structure. Furthermore, our data using neutrophil elastase (NE) knock-out mice and the NE inhibitor AZD9668 suggest that neutrophils cause this damage by releasing NE and that inhibiting NE can prevent Dox-induced cardiotoxicity. This work shows the role of neutrophils and NE in Doxorubicin-induced cardiotoxicity for the first time and suggests a new possible therapeutic intervention.

Structure-Activity Relationships of Antibody-Drug Conjugates: A Systematic Review of Chemistry on the Trastuzumab Scaffold.

Antibody-drug conjugates (ADCs) are a rapidly growing class of cancer therapeutics that seek to overcome the low therapeutic index of conventional cytotoxic agents. However, realizing this goal has been a significant challenge. ADCs comprise several independently modifiable components, including the antibody, payload, linker, and bioconjugation method. Many approaches have been developed to improve the physical properties, potency, and selectivity of ADCs. The anti-HER-2 antibody trastuzumab, first approved in 1998, has emerged as an exceptional targeting agent for ADCs, as well as a broadly used platform for testing new technologies. The extensive work in this area enables the comparison of various linker strategies, payloads, drug-to-antibody ratios (DAR), and mode of attachment. In this review, these conjugates, ranging from the first clinically approved trastuzumab ADC, ado-trastuzumab emtansine (Kadcyla), to the latest variants are described with the goal of providing a broad overview, as well as enabling the comparison of existing and emerging conjugate technologies.

Nepal measles outbreak response immunization during COVID-19: A risk-based intervention strategy.

In 2020, National Immunization Programme (NIP) of Nepal implemented a measles outbreak response immunization (ORI) campaign, which was additional to an ongoing preventive measles-rubella SIA campaign. Both campaigns were implemented during ongoing COVID-19 transmission. By April, 220 measles cases and two deaths were confirmed from eight districts of Nepal. The NIP triangulated information from surveillance (measles and COVID-19), measles immunization performance and immunity profile, programme capacities and community engagement and applied a logical decision-making framework to the collated data to inform 'Go/No-Go' decisions for ORI interventions. This was reviewed by the National Immunization Advisory Committee (NIAC) for endorsement. Outbreak response with non-selective immunization (ORI), vitamin-A administration and case management were implemented in affected municipalities of four districts, while in the remaining districts outbreak response without ORI were undertaken. The structure and iterative application of this logical framework has been described. ORI was implemented without interrupting the ongoing measles-rubella vaccination campaign which had targeted children from 9 to 59 months of age. The age group for ORI was same as SIA in one sub-district area, while for the other three sub-district areas it was from 6 months to 15 years of age. More than 32,000 persons (97% coverage) were vaccinated in ORI response. Overall measles incidence decreased by 98% after ORI. The daily incidence rate of measles was 94 times higher (95% confidence interval: 36.11 - 347.62) before the ORI compared to two weeks after ORI until year end. Close attention to surveillance and other data to inform actions and seamless collaboration between NIP and core immunization partners (WHO, UNICEF), with guidance from NIAC were key elements in successful implementation. This was an example of feasible application of the global framework for implementation of a mass vaccination campaign during COVID-19 through application of a simple decision-making logical framework.

Epidemiology and Risk Factors of Healthcare-Associated Infections in Critically Ill Patients in a Tertiary Care Teaching Hospital in Nepal: A Prospective Cohort Study.

BACKGROUND: Healthcare-associated infection (HAI) is an important public health problem, particularly in intensive care units (ICUs). We aimed to examine the epidemiology and risk factors of HAIs in our ICUs and study their microbiological profile. METHODS: We evaluated 100 consecutive patients in 3 medical and surgical ICUs of a tertiary care teaching hospital daily starting in January 2016 using the Centers for Disease Control and Prevention definitions and methods. We determined the incidence and sites of HAIs, identified the causative microorganism, and studied their antibiotic sensitivity profiles. We investigated risk factors for the development of an HAI using a multiple logistic regression model. RESULTS: Of 300 patients, 129 patients (43%) developed HAIs (55.96 HAI events per 1000 ICU-days). Pneumonia was the most common type of HAI (57, 41%). Escherichia coli was the most frequently isolated microorganism (20, 29%) and 74% of the pathogens isolated were multi-drug resistant. The presence of an invasive device (Odds Ratio, 4.29; 95% Confidence Interval, 2.52-7.51) and use of sedation (Odds Ratio, 2.24; 95% Confidence Interval, 1.31-3.87) were the statistically significant risk factors for HAIs. CONCLUSIONS: We found a high incidence of HAIs in our ICUs and a high burden of multidrug-resistant microorganisms highlighting the importance of infection control and antibiotic stewardship.

Serum Helicobacter pylori antibody reactivity in seven Asian countries using an automated latex aggregation turbidity assay.

BACKGROUND AND AIM: To determine the application range of diagnostic kits utilizing anti-Helicobacter pylori antibody, we tested a newly developed latex aggregation turbidity assay (latex) and a conventional enzyme-linked immunosorbent assay (E-plate), both containing Japanese H. pylori protein lysates as antigens, using sera from seven Asian countries. METHODS: Serum samples (1797) were obtained, and standard H. pylori infection status and atrophy status were determined by culture and histology (immunohistochemistry) using gastric biopsy samples from the same individuals. The two tests (enzyme-linked immunosorbent assay and latex) were applied, and receiver operating characteristics analysis was performed. RESULTS: Area under the curve (AUC) from the receiver operating characteristic of E-plate and latex curves were almost the same and the highest in Vietnam. The latex AUC was slightly lower than the E-plate AUC in other countries, and the difference became statistically significant in Myanmar and then Bangladesh as the lowest. To consider past infection cases, atrophy was additionally evaluated. Most of the AUCs decreased using this atrophy-evaluated status; however, the difference between the two kits was not significant in each country, but the latex AUC was better using all samples. Practical cut-off values were 3.0 U/mL in the E-test and 3.5 U/mL in the latex test, to avoid missing gastric cancer patients to the greatest extent possible. CONCLUSIONS: The kits were applicable in all countries, but new kits using regional H. pylori strains are recommended for Myanmar and Bangladesh. Use of a cut-off value lower than the best cut-off value is essential for screening gastric cancer patients.

Efficient Far-Red/Near-IR Absorbing BODIPY Photocages by Blocking Unproductive Conical Intersections.

Photocages are light-sensitive chemical protecting groups that give investigators control over activation of biomolecules using targeted light irradiation. A compelling application of far-red/near-IR absorbing photocages is their potential for deep tissue activation of biomolecules and phototherapeutics. Toward this goal, we recently reported BODIPY photocages that absorb near-IR light. However, these photocages have reduced photorelease efficiencies compared to shorter-wavelength absorbing photocages, which has hindered their application. Because photochemistry is a zero-sum competition of rates, improvement of the quantum yield of a photoreaction can be achieved either by making the desired photoreaction more efficient or by hobbling competitive decay channels. This latter strategy of inhibiting unproductive decay channels was pursued to improve the release efficiency of long-wavelength absorbing BODIPY photocages by synthesizing structures that block access to unproductive singlet internal conversion conical intersections, which have recently been located for simple BODIPY structures from excited state dynamic simulations. This strategy led to the synthesis of new conformationally restrained boron-methylated BODIPY photocages that absorb light strongly around 700 nm. In the best case, a photocage was identified with an extinction coefficient of 124000 M-1 cm-1, a quantum yield of photorelease of 3.8%, and an overall quantum efficiency of 4650 M-1 cm-1 at 680 nm. This derivative has a quantum efficiency that is 50-fold higher than the best known BODIPY photocages absorbing >600 nm, validating the effectiveness of a strategy for designing efficient photoreactions by thwarting competitive excited state decay channels. Furthermore, 1,7-diaryl substitutions were found to improve the quantum yields of photorelease by excited state participation and blocking ion pair recombination by internal nucleophilic trapping. No cellular toxicity (trypan blue exclusion) was observed at 20 µM, and photoactivation was demonstrated in HeLa cells using red light.

Immune checkpoint CD47 molecule engineered islets mitigate instant blood-mediated inflammatory reaction and show improved engraftment following intraportal transplantation.

Instant blood-mediated inflammatory reaction (IBMIR) causes significant destruction of islets transplanted intraportally. Myeloid cells are a major culprit of IBMIR. Given the critical role of CD47 as a negative checkpoint for myeloid cells, we hypothesized that the presence of CD47 on islets will minimize graft loss by mitigating IBMIR. We herein report the generation of a chimeric construct, SA-CD47, encompassing the extracellular domain of CD47 modified to include core streptavidin (SA). SA-CD47 protein was expressed in insect cells and efficiently displayed on biotin-modified mouse islet surface without a negative impact on their viability and function. Rat cells engineered with SA-CD47 were refractory to phagocytosis by mouse macrophages. SA-CD47-engineered islets showed intact structure and minimal infiltration by CD11b+ granulocytes/macrophages as compared with SA-engineered controls in an in vitro loop assay mitigating IBMIR. In a syngeneic marginal mass model of intraportal transplantation, SA-CD47-engineered islets showed better engraftment and function as compared with the SA-control group (87.5% vs 14.3%). Engraftment was associated with low levels of intrahepatic inflammatory cells and mediators of islet destruction, including high-mobility group box-1, tissue factor, and IL-1ß. These findings support the use of CD47 as an innate immune checkpoint to mitigate IBMIR for enhanced islet engraftment with translational potential.

Localized Immunomodulation with PD-L1 Results in Sustained Survival and Function of Allogeneic Islets without Chronic Immunosuppression.

Allogeneic islet transplantation is limited by adverse effects of chronic immunosuppression used to control rejection. The programmed cell death 1 pathway as an important immune checkpoint has the potential to obviate the need for chronic immunosuppression. We generated an oligomeric form of programmed cell death 1 ligand chimeric with core streptavidin (SA-PDL1) that inhibited the T effector cell response to alloantigens and converted T conventional cells into CD4+Foxp3+ T regulatory cells. The SA-PDL1 protein was effectively displayed on the surface of biotinylated mouse islets without a negative impact islet viability and insulin secretion. Transplantation of SA-PDL1-engineered islet grafts with a short course of rapamycin regimen resulted in sustained graft survival and function in >90% of allogeneic recipients over a 100-d observation period. Long-term survival was associated with increased levels of intragraft transcripts for innate and adaptive immune regulatory factors, including IDO-1, arginase-1, Foxp3, TGF-ß, IL-10, and decreased levels of proinflammatory T-bet, IL-1ß, TNF-α, and IFN-γ as assessed on day 3 posttransplantation. T cells of long-term graft recipients generated a proliferative response to donor Ags at a similar magnitude to T cells of naive animals, suggestive of the localized nature of tolerance. Immunohistochemical analyses showed intense peri-islet infiltration of T regulatory cells in long-term grafts and systemic depletion of this cell population resulted in prompt rejection. The transient display of SA-PDL1 protein on the surface of islets serves as a practical means of localized immunomodulation that accomplishes sustained graft survival in the absence of chronic immunosuppression with potential clinical implications.

Direct Photorelease of Alcohols from Boron-Alkylated BODIPY Photocages.

BODIPY photocages allow the release of substrates using visible light irradiation. They have the drawback of requiring reasonably good leaving groups for photorelease. Photorelease of alcohols is often accomplished by attachment with carbonate linkages, which upon photorelease liberate CO2 and generate the alcohol. Here, we show that boron-alkylated BODIPY photocages are capable of directly photoreleasing both aliphatic alcohols and phenols upon irradiation via photocleavage of ether linkages. Direct photorelease of a hydroxycoumarin dye was demonstrated in living HeLa cells.

Utility of Precision Medicine in the Management of Diabetes: Expert Opinion from an International Panel.

AIM: The primary objective of this review is to develop a practice-based expert group opinion on the role of precision medicine with a specific focus on sulfonylureas (SUs) in diabetes management. BACKGROUND: The clinical etiology, presentation and complications of diabetes vary from one patient to another, making the management of the disease challenging. The pre-eminent feature of diabetes mellitus (DM) are chronically elevated blood glucose concentrations; however, in clinical practice, the exclusion of autoimmunity, pregnancy, pancreatic disease or injury and rare genetic forms of diabetes is crucial. Within this framework, precision medicine provides unique insights into the risk factors and natural history of DM. Precision medicine goes beyond genomics and encompasses patient-centered care, molecular technologies and data sharing. Precision medicine has evolved in the field of diabetology. It has helped improve the efficacy of SUs, a class of drugs, which have been effectively used in the management of diabetes mellitus for decades, and it has enabled the expansion of SUs use in diabetes patients with genetic mutations. REVIEW RESULTS: After due discussions, the expert group analyzed studies that focused on the use of SUs in diabetes patients with genomic variations and rare mutations. The expert group opined that SUs are important glucose-lowering drugs and that precision medicine helps in improving the efficacy of SUs by matching them to those patients who will benefit most. CONCLUSION: Precision medicine opens new vistas for the effective use of SUs in unexpected patient populations, such as those with genetic mutations.

Study of Oxygen Saturation by Pulse Oximetry and Arterial Blood Gas in ICU Patients: A Descriptive Cross-sectional Study.

INTRODUCTION: Pulse oximetery is expected to be an indirect estimation of arterial oxygen saturation. However, there often are gaps between SpO2 and SaO2. This study aims to study on arterial oxygen saturation measured by pulse oximetry and arterial blood gas among patients admitted in intensive care unit. METHODS: It was a hospital-based descriptive cross-sectional study in which 101 patients meeting inclusion criteria were studied. SpO2 and SaO2 were measured simultaneously. Mean±SD of SpO2 and SaO2 with accuracy, sensitivity and specificity were measured. RESULTS: According to SpO2 values, out of 101 patients, 26 (25.7%) were hypoxemic and 75 (74.25%) were non-hypoxemic. The mean±SD of SaO2 and SpO2 were 93.22±7.84% and 92.85±6.33% respectively. In 21 patients with spO2 less than 90%,the mean±SD SaO2 and SpO2 were 91.63±4.92 and 87.42±2.29 respectively. In 5 patients with SpO2 less 80%, the mean±SD of SaO2 and SpO2 were: 63.40±3.43 and 71.80±4.28, respectively. In non-hypoxemic group based on SpO2 values, the mean±SD of SpO2 and SaO2 were 95.773±2.19% and 95.654±3.01%, respectively. The agreement rate of SpO2 and SaO2 was 83.2%, and sensitivity and specificity of PO were 84.6% and 83%, respectively. CONCLUSIONS: Pulse Oximetry has high accuracy in estimating oxygen saturation with sp02>90% and can be used instead of arterial blood gas.

Pancreatic islets engineered with a FasL protein induce systemic tolerance at the induction phase that evolves into long-term graft-localized immune privilege.

We have previously shown that pancreatic islets engineered to transiently display a modified form of FasL protein (SA-FasL) on their surface survive indefinitely in allogeneic recipients without a need for chronic immunosuppression. Mechanisms that confer long-term protection to allograft are yet to be elucidated. We herein demonstrated that immune protection evolves in two distinct phases; induction and maintenance. SA-FasL-engineered allogeneic islets survived indefinitely and conferred protection to a second set of donor-matched, but not third-party, unmanipulated islet grafts simultaneously transplanted under the contralateral kidney capsule. Protection at the induction phase involved a reduction in the frequency of proliferating alloreactive T cells in the graft-draining lymph nodes, and required phagocytes and TGF-ß. At the maintenance phase, immune protection evolved into graft site-restricted immune privilege as the destruction of long-surviving SA-FasL-islet grafts by streptozotocin followed by the transplantation of a second set of unmanipulated islet grafts into the same site from the donor, but not third party, resulted in indefinite survival. The induced immune privilege required both CD4+ CD25+ Foxp3+ Treg cells and persistent presence of donor antigens. Engineering cell and tissue surfaces with SA-FasL protein provides a practical, efficient, and safe means of localized immunomodulation with important implications for autoimmunity and transplantation.

BODIPY-Caged Photoactivated Inhibitors of Cathepsin B Flip the Light Switch on Cancer Cell Apoptosis.

Acquired resistance to apoptotic agents is a long-standing challenge in cancer treatment. Cathepsin B (CTSB) is an enzyme which, among many essential functions, promotes apoptosis during cellular stress through regulation of intracellular proteolytic networks on the minute time scale. Recent data indicate that CTSB inhibition may be a promising method to steer cells away from apoptotic death toward necrosis, a mechanism of cell death that can overcome resistance to apoptotic agents, stimulate an immune response and promote antitumor immunity. Unfortunately, rapid and selective intracellular inactivation of CTSB has not been possible. However, here we report on the synthesis and characterization of photochemical and biological properties of BODIPY-caged inhibitors of CTSB that are cell permeable, highly selective and activated rapidly upon exposure to visible light. Intriguingly, these compounds display tunable photophysical and biological properties based on substituents bound directly to boron. Me2BODIPY-caged compound 8 displays the dual-action capability of light-accelerated CTSB inhibition and singlet oxygen production from a singular molecular entity. The dual-action capacity of 8 leads to a rapid necrotic response in MDA-MB-231 triple negative breast cancer cells with high phototherapeutic indexes (>30) and selectivity vs noncancerous cells that neither CTSB inhibition nor photosensitization gives alone. Our work confirms that singlet oxygen production and CTSB inactivation is highly synergistic and a promising method for killing cancer cells. Furthermore, this ability to trigger intracellular inactivation of CTSB with light provides researchers with a powerful photochemical tool for probing biochemical processes on short time scales.